System method and apparatus for localized heating of tissue

ABSTRACT

System method and apparatus for accurately carrying out the in situ heating of a targeted tissue. Small implants are employed with the targeted tissue which exhibit an abrupt change of magnetic permeability at an elected Curie temperature. The permeability state of the implant is monitored utilizing a magnetometer. The implants may be formed as a setpoint temperature determining component combined with a non-magnetic heater component to enhance the tissue heating control of the system. With the system, a very accurate quantum of heat energy can be supplied to a neoplastic lesion or tissue carrying infectious disease so as to maximize the induction of heat shock proteins. The system also may be utilized in conjunction with non-magnetic arterially implanted stents for the hyperthermia therapy treatment of restenosis and in conjunction with the mending of boney tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of copending U.S. application Ser. No.11/036,276, filed Jan. 14, 2005, which is a divisional of U.S.application Ser. No. 10/310,475, now U.S. Pat. No. 6,850,804 issued Feb.1, 2005 and claims the benefit of U.S. Provisional Application No.60/349,593, filed Jan. 18, 2002, application for U.S. patent Ser. No.10/201,363 filed Jul. 23, 2002, and application for U.S. patent Ser. No.10/246,347, filed Sep. 18, 2002, and said applications are all herebyincorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Not applicable.

BACKGROUND OF THE INVENTION

A beneficial response elicited by a heating of neoplastic tissue wasreported by investigators in 1971. See the following publication in thisregard:

-   -   (1) Brit. of Cancer 25:771 (1971);        -   Cancer Research 32:1960 (1972)            While deemed beneficial, applications of such thermotherapy            initially were constrained to external surface heating. When            external applications have been employed the resultant body            structure heating has been described as having been            uncontrolled in thermal localization resulting in            temperature elevation of the whole body. Employment of            diathermy has been reported with a resultant non-destructive            inhibitory reaction. In general, no consensus by            investigators as to the efficacy of thermotherapy with            respect to tumor was present as late as the mid 1970s. See            generally:    -   (2) Europ. J. Cancer 9: 103, (1973).    -   (3) Ziet. fur Naturforschung 8, 6: 359.    -   (4) The Lancet, p. 1027 (May 3, 1975).

Notwithstanding a straightforward need for more effective techniques inthe confinement of thermotherapy to localized internally located targettissue regions, investigators have established that tumor cells may bephysiologically inhibited by elevating their temperatures above normalbody temperature, for example, 37° C. for one major population, to arange exceeding about 40° C. The compromising but beneficial resultsfurther are predicated upon that quantum of thermal exposure achieved,based upon the time interval of controlled heat application. Thus,effective thermotherapies are characterized by an applied quantum ofthermal energy established within a restrictive tissue periphery orvolume of application with an accurately controlled temperature over aneffective component of time.

One modality of thermotherapy is termed “hyperthermia” therapy, anapproach to thermal treatment at temperatures elevated within somewhatnarrow confines above normal body temperature. For instance, theelevation above a normal body temperature of 37° C. typically will fallwithin a range of 42° C. to 45° C. While higher temperature links havebeen described, hyperthermia therapy conventionally looks to affectingtissue to the beneficial effect of, for instance, negating neoplasticdevelopment, while avoiding denaturization, i.e., cell death ornecrosis. It follows that an embracing of this therapeutic modalitycalls for the application of thermal control over specific tissuevolumes.

Confinement of thermotherapy to a neoplasm-suspect target tissue volumeinternally disposed within the body without a generation of damage tohealthy surrounding tissue has been considered problematic and thus thesubject of diverse investigation. A variety of approaches towardintra-body localized heat applications has evolved. Such effortsgenerally have been based upon the application of microwave energy (U.S.Pat. No. 4,138,998); the application of acoustic wave-based systems(ultrasound); and the application of electric fields at RF frequenciesfrom transmitting antenna arrays including an application subsetutilizing inductive systems driven at relatively lower frequencies belowthe RF realm. With the former approach, thermal localization has beenevolved by developing constructive wave interference with annularphased-array antennas. (See U.S. Pat. No. 5,251,645).

Inductively-based approaches to thermotherapy systems have receivedimportant attention by investigators. The coil transmitted outputs ofthese systems generally are focused for field convergence toward thetarget tissue volume and the resultant, internally thermally affectedtissue region has been monitored in situ by thermo-responsive sensorssuch as rod-mounted thermocouples and thermistors. Typically, thosetethered heat sensors are inserted percutaneously into the target tissueregion, being coupled by extra-body electrical leads extending toconnections with temperature monitoring readouts. The invasiveness ofthe monitoring electrical leads extending into the patients' body forthis procedure has been considered undesirable. This particularly holdswhere repetitive but time-spaced procedures are called for, or thetherapeutic modality is employed in thermally treating tumor within thebrain.

Efforts to regionalize or confine therapeutic tissue heating topredefined borders or volumetric peripheries have included procedureswherein small wire or iron-containing crystals (U.S. Pat. No. 4,323,056)are implanted strategically within the tissue region of interest.Implantation is achieved with an adapted syringe instrumentality.Electromagnetic fields then are introduced to the region to inductivelyheat the implanted radiative-responsive heater components and thus evokea more regionally controlled form of thermotherapy. In one suchapproach, ferromagnetic thermoseeds have been employed which exhibitCurie temperature values somewhat falling within the desired temperaturerange for an elected thermotherapy. This achieves a form of selfregulation by operation of the system about those Curie transitions. Forinstance, as radiative excitation drives the thermoseeds to temperaturesto within the permeability based state change levels associated withattainment of a Curie temperature range, the thermoseeds become immuneto further application of external excitation energy. (See generallyU.S. Pat. No. 5,429,583). Unfortunately, the Curie transitiontemperature range of the thermoseeds is relatively broad with respect tothe desired or target temperature. See generally:

-   -   (5) Brezovich, et al., “Practical Aspects of Ferromagnetic        Thermoseed Hyperthermia.” Radiologic Clinics of North America,        27: 589-682 (1989).    -   (6) Haider, et al., “Power Absorption in Ferromagnetic Implants        from Radio Frequency Magnetic Fields and the Problem of        Optimization.” IEEE Transactions On Microwave Theory And        Techniques, 39: 1817-1827 (1991).

Thermotherapeutic approaches designed to avoid the subcutaneousinsertion of one or more temperature sensors have looked to the controlof heating using modeling methodology. These approximating modelingmethods are subject to substantial error due to differences or vagariesexhibited by the tissue of any given patient. Such differences may bedue to variations in vascularity, as well as the gradual metamorphosisof a tumor mass. The latter aspect may involve somewhat pronouncedvariations in tissue physiologic characteristics such as density. Seegenerally the following publication:

-   -   (7) Arkin, H. et al., “Recent Development In Modeling Heat        Transfer in Blood Perfused Tissue.” IEEE Transactions on        Bio-Medical Engineering, 41 (2): 97-107 (1994).

Some aspects of thermotherapy have been employed as an adjunct to theuse of chemotherapeutic agents in the treatment of tumor. Because of theprecarious blood supply or vascularity and of the high interstitialfluid presence, such agents may not be effectively delivered to achievea 100% cell necrosis. Further the tumor vessel wall may pose a barrierto such agents, and resultant non-specific delivery may lead tosignificant systemic toxicities. Studies have addressed these aspects ofchemotherapy, for instance, by the utilization of liposomes toencapsulate the chemotherapeutic agents to achieve preferential deliveryto the tumor. However the efficiencies of such delivery approaches havebeen somewhat modest. Clinically, hyperthermia therapy has been employedas a form of adjunct therapy to improve the efficiency of moreconventional modalities such as radiation therapy and chemotherapy. Forthe latter applications the thermal aspect has been used to augmentbloodstream borne release agents or liposome introduction to the tumorsite. Hyperthermia approaches have been shown to trigger agent releasefrom certain liposomes, making it possible to release liposome contentsat a heated site (U.S. Pat. Nos. 5,490,840; 5,810,888). For any suchthermotherapeutic application, an accurate temperature control at thesitus of the release is mandated. See the following publications:

-   -   (8) Kong, et al., “Efficacy of Lipsomes and Hyperthermia in a        Human Tumor Xenograft Model: Importance of Triggered Drug        Release.” Cancer Research, 60: 6950-6957 (2000).    -   (9) Chung, J. E., et al., “Thermo-Responsive Drug Delivery From        Polymeric Micelles Using Block Co-Polymers of Poly        (N-isopropylacrylamide-b-butylmethacrylate) and Poly        (butylmethacrylate), Journal of Controlled Release        (Netherlands), 62(2): 115-127 (Nov. 1, 1999).

Hyperthermia when used in conjunction with radiation treatment ofmalignant disease has been demonstrated as beneficial for destroying aspecific tumor site. Clinical data has evolved demonstrating an improvedefficacy associated with combined radiation and hyperthermia treatmentsas compared to radiation therapy alone. Such multimodal therapy conceptsalso have been extended to a combination of hyperthermia treatment withboth radiation treatment and chemotherapy (radiochemotherapy). Seegenerally:

-   -   (10) Falk et al., “Hyperthermia In Oncology” Int. J.        Hyperthermia, Vol 17, pp 1-18 (2001).

Biological mechanisms at the levels of single cells activated by heatbecame the subject of scientific interest in the early 1960s asconsequence of the apparently inadvertent temperature elevation of anincubator containing Drosophila melanogaster (fruit flies). Thesecreatures, upon being heat shocked, showed the characteristic puffsindicative of transcriptional activity and discrete loci. See thefollowing publication:

-   -   (11) Ritossa, “A New Puffing Pattern Induced By Temperature        Shock and DNP in Drosophila.” Experientia, 18: 571-573 (1962).        These heat shock loci encoding the heat shock proteins (HSPs),        became models for the study of transcriptional regulation,        stress response and evolution. The expression of HSPs may not        only be induced by heat shock, but also by other mechanisms such        as glucose deprivation and stress. Early recognized attributes        of heat shock proteins resided in their reaction to        physiologically support or reinvigorate heat damaged tissue.        (See U.S. Pat. No. 5,197,940). Perforce, this would appear to        militate against the basic function of thermotherapy when used        to carry out the denaturization of neoplastic tissue. However,        heat shock phenomena exhibit a beneficial attribute where the        thermal aspects of their application can be adequately        controlled. In this regard, evidence that HSPs, possess unique        properties that permit their use in generating specific immune        responses against cancers and infectious agents has been        uncovered. Additionally, such properties have been subjects of        investigation with respect to boney tissue repair, transplants        and other therapies. See generally the following publications:    -   (12) Anderson et al., “Heat, Heat Shock, Heat Shock Protein and        Death: A Central Link in Innate and Adoptive Immune Responses.”        Immunology Letters, 74: 35-39 (2000).    -   (13) Srivastava, et al, “Heat Shock Proteins Come of Age:

Primitive Functions Acquire New Role In an Adaptive World.” Immunity,1998; 8(6), pp. 657-665.

Beneficial thermal compromization of target tissue volumes is notentirely associated with HSP based treatments for neoplastic tissue andother applications, for instance, having been studied in connection withcertain aspects of angioplasty. Catheter-based angioplasty was firstintentionally employed in 1964 for providing a transluminal dilation ofa stenosis of an adductor hiatus with vascular disease. Balloonangioplasty of peripheral arteries followed with cautious approaches toits implementation to the dilation of stenotic segments of coronaryarteries. By 1977 the first successful percutaneous transluminalcoronary angioplasty (PTCA) was carried out. While, at the time,representing a highly promising approach to the treatment of anginapectoris, subsequent experience uncovered post-procedural complications.While PTCA had been observed to be effective in 90% or more of thesubject procedures, acute reclosure, was observed to occur inapproximately 5% of the patients. Stenosis was observed to occur in somepatients within a period of a few weeks of the dilational procedure andrestenosis was observed to occur in 15% to 43% of cases within sixmonths of angioplasty. See generally:

-   -   (14) Kaplan, et al., “Healing After Arterial Dilatation with        Radiofrequency Thermal and Non-Thermal Balloon Angioplasty        Systems.” Journal of Investigative Surgery, 6: 33-52 (1993).

In general, the remedy for immediate luminal collapse has been a resortto urgent or emergency coronary bypass graft surgery. Thus, the originalprocedural benefits attributed to PTCA were offset by the need toprovide contemporaneous standby operating room facilities and surgicalpersonnel. A variety of modalities have been introduced to avoid postPTCA collapse, including heated balloon-based therapy, (Kaplan, et al.,supra) the most predominate being the placement of a stent extendingintra-luminally across the dilational situs. Such stents currently areused in approximately 80% to 90% of all interventional cardiologyprocedures. While effective to maintain or stabilize intra-luminaldilation against the need for emergency bypass procedures, the stentsare subject to the subsequent development of in-stent stenosis orrestenosis (ISR). See generally:

-   -   (15) Holmes, Jr., “In-Stent Restenosis.” Reviews in        Cardiovascular Medicine, 2: 115-119 (2001).        Debulking of the stenotic buildup has been evaluated using laser        technology; rotational atherectomy; directional coronary        atherectomy; dualistic stent interaction (U.S. Pat. No.        6,165,209); repeated balloon implemented dilation, the        application of catheter introduced heat to the stent region        (U.S. Pat. No. 6,319,251); the catheter-borne delivery of soft        x-rays to the treated segment, sonotherapy; light activation and        local arterial wall alcohol injection.

See additionally the following publications with respect to atherectomyfor therapeutically confronting restenosis:

-   -   (16) “Bowerman, et al., “Disruption of Coronary Stent During        Artherectomy for Restenosis.” Catherization and Cardio Vascular        Diagnosis 24: 248-251 (1991).    -   (17) Meyer, et al., “Stent Wire Cutting During Coronary        Directional Atherectomy.” Clin. Coardiol,. 16: 450-452 (1993).

In each such approach, additional percutaneous intervention is calledfor. See generally the following publication:

-   -   (18) Vlielstra and Holmes, Jr., PTCA. Philadelphia: F. A. Davis        Company (Mayo Foundation) (1987).

Other approaches have been proposed including the application ofelectrical lead introduced electrical or RF applied energy to metallicstents, (U.S. Pat. No. 5,078,736); the incorporation of radioisotopeswith the stents (U.S. Pat. Nos. 6,187,037; 6,192,095); and resort todrug releasing stents (U.S. Pat. No. 6,206,916 B1). While non-invasivecontrol of ISR has been the subject of continued study, the developmentof a necessarily precise non-invasively derived control over it hasremained an elusive goal.

Another application of hyperthermia is in orthopedics, as a means tostimulate bone growth and fracture healing. There are several FDAapproved devices for stimulation of bone growth or healing, each withlimitations and side effects. Therapies include invasive electricalstimulation, electromagnetic fields, and ultrasound stimulation. Decadesold research has claimed a stimulation of bone growth by a mild increasein temperature of the boney tissue. Previous researchers have used suchmethods as inductive heating of implanted metal plates, or heating coilswrapped around the bone. The utility of these methods is limited by theinvasive nature of the surgery needed to implant the heating elementsand the inability to closely control tissue temperature. Moreover,therapeutic benefits have been inconsistent between different studiesand experimental protocols. For a summary of past work, see generally:

-   -   (19) Wootton, R. Jennings, P., King-Underwood, C., and Wood, S.        J., “The Effect of Intermittent local Heating on Fracture        Healing in the Distal Tibia of the Rabbit.” International        Orthopaedics, 14: 189-193 (1990).

A number of protocols have demonstrated a beneficial effect ofhyperthermia on bone healing. Several studies indicate temperatureaffects bone growth and remodeling after injury. Hyperthermia may bothimprove blood supply and stimulate bone metabolism and have a directeffect on bone-forming cells by inducing heat shock proteins or othercellular proteins. In one experiment, rabbit femurs were injured bydrilling and insertion of a catheter. Hyperthermia treatments were givenat four-day intervals for 2-3 weeks using focused microwave radiation.Bones which had suffered an insult as a result of the experimentalprocedure showed a greater density of osteocytes and increased bone masswhen treated with hyperthermia. Injured bones treated with hyperthermiashowed completely ossified calluses after two weeks, while theseprocesses normally take four weeks in untreated injuries. One problemwith microwave heating of bone mass is the difficulty in predicting heatdistribution patterns and maintaining the target tissue within theappropriate heat range.

When tissue is heated at too high of temperature, there can beirreversible cytotoxic effects which could damage bone and othertissues, including osteogenic cells, rather than induce healing. Certainstudies have shown that induction of mild heat shock promotes bonegrowth, while more severe heat shock inhibits bone growth. Therefore,control and monitoring of the temperature of the targeted bone tissue isimperative to achieve therapeutic benefit and avoid tissue damage.

See additionally the following publications with respect to hyperthermiafor therapeutically promoting osteogenesis:

-   -   (20) Leon, et al., “Effects of Hyperthermia on Bone. II. Heating        of Bone in vivo and Stimulation of Bone Growth.” Int. J.        Hyperthermia 9: 77-87 (1993).    -   (21) Shui, C., and Scutt, A., “Mild Heat Shock Induces        Proliferation, Alkaline Phosphatase Activity, and Mineralization        in Human Bone Marrow Stromal Cells and Mg-63 Cells In Vitro.”        Journal of Bone and Mineral Research 16: 731-741 (2001).    -   (22) Huang, C.-C., Chang, W. H., and Liu, H.-C.. “Study on the        Mechanism of Enhancing Callus Formation of Fracture by        Ultrasonic Stimulation and Microwave Hyperthermia.” Biomed. Eng.        Appl. Basis Comm. 10: 14-17 (1998).

Existing protocols for therapeutically promoting osteogenesis arelimited by the invasive nature and concomitant potential for infectionfor instance with tethered electrical stimulators; poor temperaturecontrol, and potential for tissue injury or reduced therapeutic benefit,for instance with microwave heating or other induced electromagneticfields; difficulty in effectively applying therapy to the injured bonebecause of targeting difficulties or low patient compliance withprescribed repetitive therapy.

The host immune system can be activated against infectious disease byheat shock protein chaperoned peptides in a manner similar to the effectseen against metastatic tumors. Heat shock proteins chaperoning peptidesderived from both viral and bacterial pathogens have been shown to beeffective at creating immunity against the infectious agent. Forinfectious agents for which efficacious vaccines are not currentlyavailable (especially for intracellular pathogens e.g. viruses,Mycobacerium tuberculosis or Plasmodium) HSP chaperoned peptides may beuseful for the development of novel vaccines. It is expected thatpurified HSP chaperoned peptides (e.g. gp96 complexes) used as vaccinesfor diseases caused by highly polymorphic infectious agents would beless effective against genetically distinct pathogen populations. For asummary of past work on HSP vaccines against infectious agents, seegenerally:

-   -   (23) Neiland, Thomas J. F., M. C. Agnes A. Tan, Monique        Monnee-van Muijen, Frits Koning, Ada M. Kruisbeek, and Grada M.        van Bleek, “Isolation of an immunodominant viral peptide that is        endogenously bound to stress protein gp96/GRP94.” Proc. Nat'l        Acad. Sci. USA, 93: 6135-6139 (1996).    -   (24) Heikema, A., Agsteribbe, E., Wilschut, J., Huckriede, A.,        “Generation of heat shock protein-based vaccines by        intracellular loading of gp96 with antigenic peptides.”        Immunology Letters, 57: 69-74. (1997)    -   (25) Zugel, U., Sponaas, A. M., Neckermann, J., Schoel, B., and        Kaufmann, S. H. E., “gp96-Peptide Vaccination of Mice Against        Intracellular Bacteria.” Infection and Immunity, 69: 4164-4167        (2001).    -   (26) Zugel, U., and Kaufmann, S. H. E., “Role of Heat Shock        Proteins in Protection from and Pathogenesis of Infectious        Diseases.” Clinical Microbiology Reviews, 12: 19-39 (1999).

BRIEF SUMMARY OF THE INVENTION

The present invention is addressed to method, system and apparatus foraccurately carrying out an in situ elevation of the temperature of atarget tissue volume. Accuracy is achieved using an untetheredtemperature sensor implant positionable within or adjacent to the targettissue volume using minimally invasive procedures or usingintraoperatively implanted sensors adjunctly to surgery. Such implantsmay be in the form of (1) a single macroscopic device (e.g., wire shapedimplant), (2) multiple macroscopic devices (e.g., wire shaped implants)and/or (3) multiple microscopic devices (e.g., devices in particulateform that can be injected into a volume of the tissue or attachpreferentially systemic injection using chemical binding targetingmodalities such as possible with monoclonal antibody vehicles).Positioning of macroscopic implants may be carried out utilizing animplant instrument somewhat resembling a hypodermic needle. The implantessentially sharply transitions between externally discernable states asa setpoint or target temperature is reached at the target tissue volume,and is implemented having a soft ferrite component formulated withoxides of Fe, Mn and Zn. Such formulations are elected to derive a Curiepoint temperature corresponding with the setpoint or target temperature.Thus configured, the implants exhibit a discernable permeabilityattribute until the Curie point temperature is reached, whereupon theattribute essentially disappears. Interrogation of the implant iscarried out by moving it with respect to the lines of flux of arelatively low intensity magnetic field such as the earth's magneticfield. With such field intensities, the soft ferrite components of theimplants exhibit sharp Curie transitions which, in turn, permit accuratesetpoint temperature measurements using magnetometer-based technologies.Curie transitions may be experienced within a range of from about 0.1°C. to several ° C.

The method has broad application to thermotherapy endeavors including anin vivo stimulation of heat shock proteins, a procedure having importantutility in the treatment of cancer, infectious diseases and othertherapies. As another modality, the implant is combined with anintra-luminal stent and when so combined and implanted, permits anon-invasive repeatable and accurate hyperthermia therapy forrestenosis.

In situ heating is carried out using conventional alternating currentfield-based devices such as RF heating, inductive heating,microwave-based procedures and ultrasound, all of which are of anon-invasive nature.

The volumetrically defined heating of a target tissue may be facilitatedthrough the utilization of implanted non-magnetic heater components.These heater components may be combined with the sensor components inintimate thermal exchange relationship. In this regard, a variety ofsuch structures are described. In one approach, both the heatercomponent and the temperature sensing component are each of generallysemi-cylindrical form having the semi-cylindrically defined flatsurfaces of such geometric structures coupled together in the noted heatexchange relationship. The entire structure may be coated with anelectrically insulative biocompatible conformal coating. Additionally,the implant may carry a thermally activatable release agent layer whichfunctions to release a therapy supporting agent at the situs of thetarget tissue when the heater component reaches an induced temperatureat a setpoint temperature detected by the temperature sensing component.In another combined implant approach, the heater component is formed asa discontinuity containing covering of the sensor which, for instance,may assume a cylindrical geometric shape. The discontinuities permitinteraction of the sensor component with the monitoring magnetic field.In another approach, the cylindrical sensor component may be surmountedby a heater component which is configured as a generally open, spiralsleeve positioned against the surface of the temperature sensor inthermal exchange relationship. This defines a helical-shaped open,outwardly exposed surface portion of the sensor component, againfunctioning in conjunction with a magnetic field to provide adiscernable magnetic permeability state change at a desired setpointtemperature. Another geometry for the combinational implant provides agenerally cylindrical temperature sensor component with combined heatercomponents configured as metal caps which fit over the sensors adjacentthe ends of their cylindrical structures. Several such sensors may becombined with such end caps and intermediately disposed heater componentsleeves to, in effect, develop an implant formed of a chain of sensorswhich, for example, may be configured to exhibit a permeability statechange at different setpoint temperatures.

The implants may perform in conjunction with a variety of systemscenarios. In one approach a single channel magnetometer is employed inconjunction with a single channel pick-up. This pick-up is locatedexternally of the patient's body at a location in somewhat closeadjacency with the position of the implant. Additionally, thebroadcasting component of an alternating current field heating assemblyis positioned in adjacency with that targeted area. To carry outdetection of the permeability state of the sensor component of theimplant, the patient will be supported on an oscillative platform orchair in order to achieve single channel detection of a magneticpermeability Curie temperature state change. Either the earth's magneticfield or an applied magnetic field may be employed with this system. Inanother system approach a multi-channel magnetometer assembly isemployed incorporating an arrayed pick-up. With this arrangement thepatient support may remain stationary and the magnetometer-baseddetection assembly determines a differentiation of magnetic fielddisturbance and non-disturbance in association with the minor butinherent movement of a living animal body. In the presence of anon-disturbance condition, the target temperature or setpointtemperature at the targeted tissue will have been achieved.

A feature of the system and method of the invention is concerned with atypical patient management regimen wherein a relatively substantialrepetition of hyperthermia therapeutic procedures are called for. Theimplants remain in position with respect to the target tissue volume andmay, in this regard, be fashioned with implant barbs or the like for thepurpose of migration avoidance. Where a succession of treatments isinvolved, not only is there no requirement to re-install sensors, butalso, the aligning of the sensing system magnetometer remains quitesimple, involving the observation of signal response amplitudes on thepart of the attending technician. Another aspect of this feature residesin the utilization of the pre-implanted sensors or sensor-heaters as aconventional tumor situs marker for subsequent patient evaluationimaging procedures.

While any of the above approaches may be used in connection with stentsand the treatment for restenosis, where the stent along with temperaturesensor is implanted in a coronary artery, then the natural beating ofthe heart of the patient will provide sufficient movement of the sensoritself to permit single channel detection by a magnetometer.

Control over the alternating current field (ACF) heating systempreferably is achieved by controlling the actuation of the heatingassembly and the magnetometer in an intermittent manner. With thisapproach, the heater assembly is activated for a predetermined intervalof time following which the magnetometer is activated for a much shorterinterval. This sequencing continues until setpoint temperature isdetected, whereupon the magnetometer remains enabled while the heaterremains deactuated until the temperature sensing component reverts to ahigher relative permeability to again disturb the monitored magneticfield.

The implant controlled heating approach of the invention also may beapplied to the field of orthopedics. In this regard, the sensorcomponent may be combined in intimate thermal exchange relationship withnon-magnetic metal bone support devices implanted within boney tissue.The setpoint temperature elected for such modality is selected toenhance the repair of the mending boney tissue.

Implant based controlled in vivo heating according to the precepts ofthe invention also may be employed as a vehicle for inducing immunityagainst or for the treatment of diseases caused by infectious agents.

Other objects of the invention will, in part, be obvious and will, inpart appear hereinafter;

The invention, accordingly, comprises the method, system and apparatuspossessing the construction, combination of elements, arrangement ofparts and steps which are exemplified in the following detaileddescription.

For a fuller understanding of the nature and objects of the invention,reference should be made to the following detailed description taken inconnection with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a partial schematic view of a prior art approach to heating atarget tissue volume utilizing an auto-regulating heater implant;

FIG. 2 shows curves relating relative permeability with temperature forferromagnetic implants;

FIG. 3 is a generalized semi-log curve illustrating the temporalrelationship between the duration of application of a given temperatureto tissue with the value of critical temperatures;

FIG. 4 is a prior art approach to heating a targeted tissue volumeutilizing tethered heat sensors located within the target tissue volume;

FIG. 5 is a schematic representation of one embodiment of the system ofthe invention utilizing a patient moving mechanism;

FIG. 6 is a schematic depiction of a fluxgate sensor;

FIG. 7 is a chart illustrating the intermittent heating andinterrogating features of the system of the invention, the chart beingbroken along its timeline in the interest of clarity;

FIGS. 8A and 8B combine as labeled thereon to provide a schematic blockdiagram of a control feature of the invention;

FIG. 9 is a general view of an implant incorporating heater and sensorcomponents according to the invention;

FIG. 9A is a perspective view of an implant configured in accordancewith FIG. 9 but modified to incorporate extensible barb-like structuresfor migration avoidance;

FIG. 10 is a sectional view of the implant of FIG. 9;

FIG. 11 is a sectional view taken through the plane 11-11 shown in FIG.10;

FIG. 12 is a sectional view of the implant of FIG. 9 showing theincorporation of a heat activated release agent coating;

FIG. 13 is a sectional view taken through the plane of 13-13 shown inFIG. 12;

FIG. 14 is a perspective view of another embodiment of an implantaccording to the invention with a combined heater component and sensorcomponent;

FIG. 14A is a perspective view of an implant configured in accordancewith FIG. 14 but modified to incorporate extensible barb-like structuresfor migration avoidance;

FIG. 15 is a sectional view of the implant of FIG. 14;

FIG. 16 is a sectional view taken through the plane 16-16 shown in FIG.15;

FIG. 17 is a sectional view of the implant of FIG. 14 showing theincorporation therewith of a heat activated release agent coating;

FIG. 18 is-a sectional view taken through the plane 18-18 in FIG. 17;

FIG. 19 is another embodiment of an implant according to the inventionincorporating both sensor and heater components;

FIG. 19A is a perspective view of an implant configured in accordancewith FIG. 19 but modified to incorporate extensible barb-like structuresfor migration avoidance;

FIG. 19B is a perspective view of an implant configured in accordancewith FIG. 19 but modified to provide a heater component as extendinginto a spiral tissue engaging implement.

FIG. 19C is a perspective view of an implant configured in accordancewith FIG. 19 but modified to incorporate a heater component configuredas a screw thread for tissue engagement;

FIG. 19D is a perspective view of an implant having a sensor componentconfigured in accordance with that of FIG. 19 but incorporating a heatercomponent formed as a sequence of disk-like structures functioning toanchor the implant within tissue;

FIG. 20 is a sectional view of the implant of FIG. 19;

FIG. 21 is a sectional view taken through the plane 21-21 shown in FIG.20;

FIG. 22 is a perspective view of another implant according to theinvention incorporating both sensor and heater components;

FIG. 23 is a sectional view of the implant of FIG. 22;

FIG. 24 is a perspective view of another implant embodiment according tothe invention incorporating both sensor and heater component;

FIG. 24A is a perspective view of an implant configured in accordancewith FIG. 24 but modified to incorporate extensible barb-like structuresfor migration avoidance;

FIG. 25 is a sectional view of the implant of FIG. 24;

FIG. 26 is a sectional view of the implant of FIG. 24 showingincorporation of a thermally activated release agent coating;

FIG. 27 is a perspective view of an implant according to the inventionincorporating only a sensor function;

FIG. 28 is a sectional view of the implant of FIG. 27;

FIG. 29 is a sectional view of the implant of FIG. 28 taken through theplane 29-29 shown therein; - FIG. 30 is a sectional view of the implantof FIG. 27 showing the incorporation therewith of a thermally activatedrelease agent coating;

FIG. 31 is a sectional view taken through the plane 31-31 shown in FIG.30;

FIG. 32 is a schematic and sectional view of an implant locatinginstrument which may be used with the implants of the invention showingthe instrument prior to releasing the implant in a targeted tissuevolume;

FIG. 33 is a schematic sectional view of the instrument of FIG. 32showing the delivery of a sensor implant into a targeted tissue volume;

FIG. 34 is a flow chart depicting a process for the manufacture offerrites;

FIG. 35 is a curve relating relative permeability with temperature;

FIGS. 36A-36G combine as labeled thereon to provide a flowchartillustrating the procedure and control carried out with the systemrepresented in FIG. 5;

FIG. 37 is a sectional schematic representation of a prior art approachto applying thermotherapy to a stent imbedded in a blood vessel;

FIG. 38 is a sectional view taken through the plane 38-38 shown in FIG.37;

FIG. 39 is a schematic sectional representation of a combined stent andsensor component assembly according to the invention imbedded within ablood vessel;

FIG. 40 is a sectional view taken through the plane 40-40 shown in FIG.39;

FIG. 41 is a schematic representation of a system according to theinvention for utilization of stents formed according to the invention;

FIG. 42 is a sectional schematic view of a stent according to theinvention incorporating a heat activated release agent coating and beingshown imbedded within a blood vessel;

FIG. 43 is a sectional view taken through the plane 43-43 shown in FIG.42;

FIG. 44 is a schematic sectional view of another stent embodimentaccording to the invention, the device being shown embedded within ablood vessel;

FIG. 45 is a sectional view taken through the plane 45-45 shown in FIG.44;

FIG. 46 is a sectional schematic view of a stent embedded in a bloodvessel and having been retrofitted with a sensor assembly according tothe invention;

FIG. 47 is a sectional view taken through the plane 47-47 shown in FIG.46;

FIG. 48 is a sectional schematic view of a stent embedded within a bloodvessel and showing a retrofit thereof with two sensor assembliesaccording to the invention;

FIG. 49 is a sectional view taken through the plane 49-49 shown in FIG.48;

FIGS. 50A-50F combine as labeled thereon to provide a procedure andcontrol flowchart associated with the system shown in FIG. 41;

FIG. 51 is a schematic representation of another embodiment of thesystem of the invention showing the utilization of a stationary patientsupport in combination with a multichannel magnetometer having an arrayof pick-ups;

FIGS. 52A-52F combine as labeled thereon to provide a procedure andcontrol flowchart associated with the system illustrated in connectionwith FIG. 51;

FIG. 53 is a diagram showing a system of the invention wherein thepatient is held stationary and a stent is thermally treated utilizing amultichannel magnetometer with an array of pick-ups, the diagram furthershowing an alternative arrangement utilizing a single channelmagnetometer and pick-up and relying upon relative movement of thesensor by virtue of adjacent heartbeat activity;

FIGS. 54A-54E combine as labeled thereon to describe the control andprocedure associated with the system illustrated in connection with theFIG. 53;

FIG. 55 is a schematic diagram of a system according to the inventionwherein the patient remains stationary while a multi-channelmagnetometer evaluates an implant in combination with anelectromagnetically generated magnetic field;

FIGS. 56A-56B combine as labeled thereon to provide a block diagrammaticillustration of the control features of the system of FIG. 55; and

FIGS. 57A-57G combine as labeled thereon to provide a procedure andcontrol flowchart describing the system illustrated in connection withFIG. 55.

DETAILED DESCRIPTION OF THE INVENTION

While a variety of techniques for evolving an effective interstitialthermotherapy of target tissue volumes have been approached byinvestigators, an earlier development deemed somewhat promising involvedthe implantation of ferromagnetic alloy heaters sometimes referred to as“ferromagnetic seeds” within that volume. The ferromagnetic alloyheaters were adapted so as to alter in exhibited magnetic permeabilityin consequence of temperature. For example, with this arrangement, whena Curie temperature transition range was thermally reached, permeabilitywould, in turn, diminish over the transition range and correspondinglythermal responsiveness to an applied inductive field-would diminish.Thus it was opined that a temperature auto-regulation could be achievedto optimize a thermally based implantation therapy. Such an arrangementis depicted in FIG. 1. Here, the treatment modality is representedgenerally at 10 wherein a target tissue volume, for example, comprisedof neoplastic tissue, is shown symbolically within dashed region 12located internally within the body of patient 14. Within the targettissue volume 12 a ferromagnetic material (e.g., having palladium cobaltadditives) auto-regulating heater implant 16 is embedded which is, forinstance, inductively heated from the excited inductive coil 18 of analternating current field (ACF) heating assembly 20. The ferromagneticimplants as at 16 exhibit a temperature-related relative magneticpermeability, μ_(r). Such relative permeability may be represented bycurve 22 shown in FIG. 2. Relative permeability is expressed asμ_(r)=μ/μ_(o), where μ=absolute permeability (Henry/meter), μ_(o)=aconstant=magnetic permeability of free space (Henry/meter) and μ_(r) istherefore dimensionless but ranges from a value of unity to 100,000 ormore. Curve 22 reveals that the relative magnetic permeability, μ_(r),decreases as the temperature of the ferromagnetic alloy heaterapproaches its Curie temperature, T_(c). Since the induced electricfield heating power in an object is proportional to the square root ofmagnetic permeability, a decrease in magnetic permeability withelevation of temperature is associated with a corresponding decrease inthe heating power associated with inductive heating.

Traditionally, the change in magnetic permeability of ferromagneticalloys with increasing temperature has not been abrupt as would bepreferred for precise temperature regulation of an implanted heatingcomponent as at 16. In this regard, characteristic curve 22 reveals thatunder the relatively intense, applied fields a permeability transitionoccurs gradually over a span typically of 10° C. to 15° C. or more. As aresult, the implanted heater device 16 may not reach the intended Curietemperature and resultant relative permeability of unity. Often, thatelevation in temperature above normal body temperature has not beenachieved. Accordingly, accommodation has been made by electing Curietemperature transition ranges falling well above what would haveotherwise been a target temperature for thermotherapy with a result thatcritical temperature limits of the tissue being treated have beenexceeded. Thermotherapeutic procedures also are prone to inaccuracies byvirtue of the unknown environmental conditions within which an implantas at 16 is situated. With respect to such unknown phenomena,temperatures achieved with ferromagnetic implants will vary dependingupon cooling phenomena within the tissue surrounding the device. Suchphenomena occur, for example, as a consequence of the degree ofvascularity in the target region and proximity of the heating element asat 16 to blood vessels. These vessels will tend to perform as inherentcooling mechanisms. Accordingly, while attempting to achieve aneffective heat therapy, the auto-regulating implants as at 16 generallyhave been unable to establish a necessary precise temperature output forrequisite therapeutic time intervals.

Now turning to the subject of the physiological consequence of elevatingtissue temperature, studies have been carried out to investigate boththe component of temperature elevation as well as the time componentwithin which such asserted higher temperatures are maintained, i.e., thetemporal aspect thereof. Such investigations have established criticaltemperature and time relationships which identify the occurrence ofirreversible tissue damage effects. In this regard, looking to FIG. 3, ageneralized semi-log curve 24 is presented illustrating the temporalrelationship between the duration of the application of a giventemperature to tissue with the value of that critical temperature atwhich irreversible tissue damage may occur. The system and method of thepresent invention are concerned, inter alia, with maintaining thetreatment of target tissue volumes at accurately controlled temperaturesfor heat-based therapies including hyperthermia. Hyperthermia is a formof thermotherapy where there is an artificial elevation of thetemperature of a group of cells, a tissue, cell culture, or a wholeorganism for experimental or therapeutic purposes. Heating of tissuethrough thermotherapy techniques can induce a variety of biologicresponses, depending on the intensity of the stress induced. When atissue is heated, certain cells near the focus of the induced heatingmay experience greater heat shock than cells at a distance from thefocus. Therefore, within a tissue being heated, a range of responses mayoccur at the cellular level. These responses of tissues to hyperthermiacan be broadly categorized. If the heat shock is too mild, there will beno detectable biologic changes (over the basal level of “heat shock”gene expression typical in the absence of heat shock). A mild heat shockmay induce reversible cellular changes, including, for example,reversible denaturation of proteins, triggering of ion fluxes fromvarious cellular compartments, activation of existing enzymes, andimportantly, induction of alterations in gene expression.

A more severe-heat shock may irreversibly damage cellular components.Under certain conditions, when a cell is damaged, an ordered process,apoptosis, is induced that leads to the death of the damaged cell.Apoptosis is considered a form of “programmed cell death,” and cellsundergoing apoptosis often exhibit distinctive morphologic changes.Apoptosis is also involved in many developmental processes, defensiveresponses to microbial infection, the homeostasis of cell populations(e.g. lymphocytes) and as means of eliminating genetically damagedcells, such as cancer cells.

It is generally accepted that apoptosis is an active, highly organized,form of cell death, requiring both RNA and protein synthesis. A classicexample is the systematic death of a finite number of cells, 131, at acertain stage in the life cycle of the nematode Caenorhabditis elegans,a process controlled by the negative and positive regulation of specificgenes. As demonstrated by development in C. elegans, certain genes areinvolved in the regulation of cell death by apoptosis. A specificexample is the human gene bcl-2. In certain human follicular B-celllymphomas, deregulation of the expression of bcl-2 has been identifiedas a cause of the prolonged survival of the lymphoma cells. Alteredexpression of bcl-2 interferes with the typical programmed cell deathpattern, blocking apoptosis even when hematopoeitic growth factors areabsent.

Apoptotic cells exhibit a pronounced decrease in cellular volume,modification of the cytoskeleton that results in convolution of thecell, and eventual blebbing of the cell's membrane, compaction ofchromatin and its segregation within the nucleus that the cell. The DNAis degraded into small fragments, and the apoptotic cell sheds smallmembrane-bound apoptotic bodies which may contain intact organelles. Theapoptotic bodies are phagocytosed (e.g. by macrophages) and the contentsof apoptotic bodies are intracellularly degraded, with little release ofthe contents of the apoptotic cells. In this manner, apoptosis does notinduce a localized inflammatory response.

Apoptosis is differentiated from necrosis by the general absence ofinflammation. It is a physiological type of cell death, part of ahomeostatic mechanism to maintain an optimal number and arrangement ofcells. In certain physiological conditions, massive apoptosis is notfollowed by necrosis and inflammation, such as the removal ofinterdigital webs during early human development, the regression ofliver hyperplasia following withdrawal of a primary mitogen [Columbanociting Bursch, Carcinogenesis 5: 453-458.], and cellular loss in thepremenstrual endometrium.

If thermotherapy is sufficiently severe, cells and tissues may be sodamaged that cellular integrity is destroyed, or the cellular machineryis so disabled that the induction of apoptosis does not occur. Incontrast to apoptosis, necrosis is a type of cell death morphologicallycharacterized by extensive cell loss, which results in the recruitmentof inflammatory cells. In necrosis, injured cells may exhibit clumpingof chromatin, swelling of the cell and organelles (demonstrating a lossof control of ion balance), flocculent mitochondria, and eventualbursting and disintegration of the necrotic cell. If necrosis isextensive enough, the architecture of a tissue is destroyed. Extensivenecrosis is characteristic of tissue destruction induced followingsevere damage by toxic chemicals, invasive microorganisms or ischemia.The wholesale release of cellular components into a tissue itself cantrigger a damaging inflammatory response.

When a tissue is damaged, cells may die by a combination of apoptosisand necrosis. Many agents capable of inducing necrosis also induceapoptosis. Apoptosis often precedes extensive necrosis, with apoptosisin these situations possibly acting in a self-protective manner. Whenthe level of insult to a tissue is too great, necrotic cell death cannotbe avoided. Murine mastocytoma cells have been reported to undergoapoptosis after a moderately severe heat shock, but the same cells dievia necrosis when the heat shock exposure is more severe.

For a comparison of apoptosis and necrosis, see:

-   -   (27) Columbano, A., “Cell Death: Current Difficulties in        Discriminating Apoptosis from Necrosis in Context of        Pathological Processes in vivo.” Journal of Cellular        Biochemistry, 58: 181-190 (1995).

The cellular response to a heat-shock has been extensively studied.Certain heat shock inducible proteins such as Heat Shock Protein 70(HSP70), HSP 90 and gp96 are expressed constitutively at low levels.During mild to moderate heat-shock, cellular proteins may undergoconformational changes. It is this alteration in the structure ofproteins, or other reversible denaturation effects, which are believedto play a role in inducing the heat shock response. (Note that otherstressors, such as nutrient deprivation, release of oxygen radicals, orviral infection may also induce conformational aberrations.) Following aheat shock, mRNA expression of the genes encoding HSP70, HSP 90 andgp96, for example (along with that of other heat-shock responsive genes)is induced by activating proteins called “Heat Shock Factors.” Theresponse of two “Heat Shock Factors”, HSF-I and HSF-II is triggered bydifferent levels of thermal stress. As an example, HSP70 is thought tobe induced more rapidly than (by either less heat stress, or a shorterduration) HSP90. Therefore, different thermotherapy regimes will inducedifferent panels of heat inducible genes.

For additional background on the heat shock response see:

-   -   (28) Georgopoulos, C., Welch, W. J. “Role of the Major Heat        Shock Proteins as Molecular Chaperones.” Annu. Rev. of Cell        Biol., 9: 601-634 (1993).    -   (29) Hendrick, J. P. and Hartl, F. U., “Molecular Chaperone        Functions of Heat-Shock Proteins.” Annu. Rev. of Biochem., 62:        349-84 (1993).    -   (30) Lindquist, S., “The Heat Shock Response.” Annu. Rev.        Biochem., 55: 1151-91 (1986).    -   (31) Matzinger, “Tolerance and Danger: the Sensitivity of the        Immune System.” Annu. Rev. Immunol., 12: 991-1044 (1994).    -   (32) Morimoto R. I., “Perspective: Cells in Stress:        Transcriptional Activation of Heat Shock Genes.” Science 259:        1409-10 (1993).    -   (33) Morimoto, R. I., “Stress Inducible Responses”, Springer        Verlag, Boston (1996)    -   (34) Parsell, D. A. & Lindquist, S., “The Function of Heat-Shock        Proteins in Stress Tolerance: Degradation and Reactivation of        Damaged Proteins.” Annu. Rev. of Genet., 27: 437-496 (1993).    -   (35) Schlesinger, M. J., “Minireview: Heat Shock Proteins.”        Journal of Biological Chemistry 265: 12111-12114 (1990).

Initiation of a heat-shock will induce conformational changes incellular proteins, and lead to the induction of heat shock genes. HSP70has the ability to bind to proteins, is thought to act as a molecularchaperone, and may use an ATP dependant activity to renaturestress-damaged proteins. It is thought that HSP 70 is involved in aprocess that ‘repairs’ partially denatured proteins. If the nativeconformation of a protein is not restored, then the denatured protein isdegraded. During the degradation process, HSP70 can retain a peptidefragment derived from the degraded protein. In essence HSP 70 may thenchaperone an antigenic peptide fragment of the denatured protein. TheseHSP70 chaperoned fragments are then processed though the cell'sendoplasmic reticulum and Golgi apparatus, and can then appear on thecell surface, presented by MHC-I molecules. Antigens presented on thesurface of a cell can then lead to an immune response being generated tothose antigens.

In order to have processing of peptide fragments, and presentment ofpotentially immunogenic fragments on the cell surface, it is necessaryto have a living cell. An apoptotic cell, since the cellular contentsare degraded (for instance, without presenting antigens on thephagocytitic cell's surface MHC-I molecules), may have lowerimmunogenicity than either a heat shocked, but recovering cell or anecrotic cell.

Accordingly, with accurate temperature and time controls therapyemploying heat shock protein induction becomes available. Other adjuncttherapies available with accurately controlled thermotherapy are, forexample, release agent systems associated with a heating instigatedrelease, radiation treatment, chemotherapy and radiochemotherapy.

Some approaches utilized by investigators, in the use of hyperthermiatherapy, have achieved accurate temperature measurement and consequentcontrol by inserting temperature sensors such as fiber optic temperaturesensors, thermocouples or thermistors into the tissue adjacent to orintegrally with implanted heaters. These fiberoptic, thermocouple orthermistor-based sensors necessarily are tethered having one or moreelectrical or optical leads extending externally or to a surface regionof the body each time a hyperthermia therapy is administered. In thelatter regard, the somewhat involved procedure often must also berepeated a number of times over many weeks or months to effect thedesired therapeutic results. This becomes particularly problematic wherethe approach is employed in thermal therapy procedures associated withthe human brain. See generally:

-   -   (36) Hynynen, et al., “Hyperthermia in Cancer Treatment.”        Investigative Radiology, 25: 824-834 (1990)

Referring to FIG. 4, the noted tethered approach to sensing internaltarget tissue volume subjected to thermal therapy is illustratedschematically. In the figure, a targeted internal tissue volume 26 ofpatient 28 is shown to be under thermotherapy treatment. Thermal energyis applied to the target tissue volume 26 from the heating coil orantenna 30 of an ACF heating assembly employing radio frequency (RF) ormicrowave based heating as represented at block 32. The coil or antenna30 typically is of a design based upon human phantom models and/orcomputer modeling achieving a coil/antenna structuring which evokes thesought after heating and thermal distribution at the target tissuevolume 26. One or more temperature sensors 34 a-34 d are implantedstrategically within the target tissue volume 26. Devices 34 a-34 d are“tethered” in that electrical leads 34 a-34 d extend therefrom throughor adjacent to the skin to a temperature monitor/controller 38.Controller 38 additionally controls the output of the heating assembly32 as is represented by arrow 40. In general, the heating carried out bythe heating unit 32 may be enhanced through the utilization of heatingelements implanted within the zone of the target tissue volume 26. Aprincipal limitation of the technique illustrated in connection withFIG. 4 resides in the requirement that the temperature sensors 34 a-34 dmust be inserted into and accurately positioned within the patient 28each time thermotherapy is carried out and the procedure may be repeatedoften; calling for a succession of accurate sensor positionings. Asnoted earlier, the somewhat arduous insertion of the heat sensingelements 34 a-34 e becomes particularly intrusively undesirable wherethe procedure is carried out in conjunction with brain tumor.

Should those sensors as at 34 a-34 d not be utilized, the temperaturesreached at the target tissue volume 26 during application of ACFradiofrequency or microwave heating can only be approximated by modelingmethods which are subject to substantial error due to physicaldifferences in the tissue of given patients. In this regard, tissueswill exhibit differences in vascularity, as well as otherwise assumedaverage properties. As noted hereinbefore, vascularity functions as aconveyance for heat removal in the vicinity of the targeted tissueregion. For further discussion of thermal modeling based methods ofthermotherapy, reference is made to publication (7) supra.

The present invention-generally is characterized by the partitioning ofthe function of heating the target tissue volume to requisitetemperatures from the function of measurement of tissue temperature. Forthe latter function, the remotely interrogatable material property ofmagnetic permeability can achieve accurate temperature measurement oververy narrow temperature ranges, for example, between about 0.1° C. toabout 1° C. Untethered implanted soft ferromagnetic sensors areemployed, which are of diminutive size and can be structured to providesuch a very sharp Curie transition. For example, a transition ofrelative magnetic permeability, Pr, from about 100 to 1000 to 1 obtains.Returning to FIG. 2, the relative permeability/temperaturecharacteristic achieved with a soft ferrite under relatively lowmagnetic field intensities (earth's magnetic field) is represented bydashed curve 42. Note that curve 42 exhibits a Curie point transition atknee 44. This narrow transition range is generally represented at arrowpair 46.

See generally the following publications;

-   -   (37) Yoshifumi, A., et al., “Preparation and Evaluation of        Temperature Sensitive Magnetic Thin Film With Low Curie        Temperature”, T. IEE Japan, Vol. 118-A, No. 2, 1998, pp 158-163.    -   (38) Goldman, “Handbook Of Modern Ferromagnetic Materials”,        1999, Kluwer Academic Publishers, Norwell, Mass.        Because the sensors at hand are of such small size the        methodology of the invention can be employed in conjunction with        magnetic resonant imagining (MRI) without adverse consequence.        In effect, the very narrow Curie transition permits a “binary”        response tuned to a particular predetermined target temperature        for the involved target tissue volume. The instant system and        method may provide a separate, nonmagnetic heater material which        is thermally exercised from a remote non-invasive radiative        source and which is brought into close thermal communication        with a sensor component. In this manner, precise temperature        sensing and control can be achieved, inasmuch as, for example,        the soft ferromagnetic materials employed can be selected for        their very sharp change in magnetic permeability over a narrow        Curie temperature transition range while performing under        relatively low magnetic field intensities.

The heater materials employed with these sensors are selected frommaterials which are non-magnetic so as to permit their performance withsensors having magnetic properties. With the combination of a heatingcomponent with a sensor structure formed with a narrow Curietransition-based material, precise setpoint temperatures can be detectednon-invasively using magnetometer technology in conjunction with lowintensity magnetic fields such as the earth's magnetic field as it isinfluenced or perturbed by confrontation with the sensing component.Such magnetometer monitoring can be carried out in one approach byevoking relative movement of the target tissue volume with respect tothe position of influence of the magnetometer and in another approachthrough the use of detector arrays. Alternately the system may performwith a derived magnetic field, for example, one which iselectromagnetically generated.

Referring to FIG. 5, a schematic representation of one embodiment of thesystem of the invention is provided. In the figure, a patient 50 isshown in a supinate position on the horizontal platform 52 of a supportassemblage represented generally at 54. Platform 52 is moveablysupported within the assemblage 54 by a plurality of roller bearingscertain of which are identified at 56 . Bearings 56, in turn, are shownmounted upon a translational support structure 58. As represented by thedual arrow 60, platform 52 may be caused to oscillate along a linearhorizontal locus in consequence of its oscillatory actuation by a driveassembly represented generally at 64. Assembly 64 includes anoscillatively drivable motor 66 coupled via a drive collar 68 with aball-screw mechanism represented generally at 70. Mechanism 70 includesa lead screw 72 which is threadably connected with abearing-incorporating drive collar 74 fixed in turn to the platform 52.Lead screw 72 terminates in a thrust bearing 76. Oscillatory drive inputto the motor 66 is provided from a motor control circuit 78 asrepresented by dual arrows 80. Line power is supplied to the motor 66via the control circuit 78 as represented by arrow 82 and control inputas well as status feedback information is represented by enlarged dualdirectional arrow 84. The oscillatory function provided by the supportassemblage 54 can take a variety of support configurations dependingupon, for instance, the region of tissue interest involved with theprocedure. In this regard, a variety of chair structures can beimplemented with the oscillatory function with patient 50 assuming otherthan the illustrated supinate posture. The amount of oscillationprovided by the support assemblage 54 as represented by dual arrow 60may be quite minimal, for example, an amplitude of oscillation of about0.3 cm to about 10 cm may be provided at an oscillatory rate of about0.1 cm to about 3 cm per second. In general, frequency is selected inaccordance with the relative strength of the earths' magnetic field aswill be seen to be employed with the instant embodiment, and the lengthof travel along the linear locus may be established in consonance withthe dimensions of the target tissue volume involved. In the latterregard, the system is called upon to traverse at least that tissuevolume defined distance in the presence of a magnetic field evaluationpick-up. Because the system employs a magnetometer with pick-up,pertinent components of the support system 54 are constructed ofnon-magnetic materials such as plastic, and the like to preventinterference with magnetic field-based measurement.

The target tissue volume of interest for the instant embodiment isrepresented internally within the body of patient 50 by a symbolicallyrepresented dashed boundary 90. Within this boundary 90 there is shownat least one sensor implant configured according to the invention asrepresented schematically at 92. However, that sensor implant orcombination of such implants may be intimately combined with aninternally disposed nonmagnetic heating component. Where those twocomponents are combined in a single implant arrangement, at least aportion of the surface of both the nonmagnetic heating component andsensor component are exposed. Note that the implant 92 is untethered,having no electrical leads extending exteriorly of the patient 50.

Heating of the region of interest 90 under thermotherapy conditions and,in particular, hyperthermia conditions for the instant system, isprovided from an inductive form of alternating current field (ACF)heating assembly represented at block 94. Line power input isrepresented as being directed to the assembly 94 as indicated at arrow96. Substantially focused radiative heating is provided from the heatingassembly 94 by a typical coil-implemented heating component representedat 98 which is positioned in close proximity to the skin of patient 50in the vicinity of a predetermined and earlier marked location of thetarget tissue volume 90. Association of the component 98 with theheating assembly 94 is represented schematically by line pair 100.Preferably, the component 98 may be associated with an induction heatingassemblage operating at a lower frequency within the generallyidentified radiofrequency range. In the latter regard, such an inductionheating arrangement may be provided, for example, as a type NK-24induction heating system marketed by Pillar Industries, Inc., ofBrookfield, Wis. Other radiative heating systems will include thoseemploying higher frequency RF, microwave or ultrasound technologies.(See f, in Table 1). As used herein, the terms “alternating currentfield” or “ACF” are meant to include radiofrequency (RF) systems,inductive systems, microwave systems, ultrasound systems and othernon-invasive heating approaches which may perform in concert withuntethered temperature sensors.

Now looking to the magnetometer-based detection of the magnetic fielddisturbances evoked by the state of permeability of the sensor componentat implant 92, a magnetometer control assembly is represented at block104. The assembly 104 performs in conjunction with a remotely disposedpick-up or probe 106 oriented for discerning and/or differentiatingmagnetic field flux lines as they may be affected by the implant orimplants as at 92. The association of probe or pick-up 106 with theassembly 104 is represented at cable 108. Assembly 104 is seen receivingline power, as represented by arrow 110, and is controlled and providesoutputs to a console mounted control assembly represented generally at112 as indicated at arrow 114. It may be noted that the control assembly112 also is in communication with the motor control 78 as represented atarrow 84 and with the ACF heating assembly 94 as represented at arrow102. While the magnetometer assembly 104 with its probe 106 may performwith a generated and applied magnetic field, for the instant embodiment,the field utilized is the earth's magnetic field. Because of the on/offor binary nature of the temperature sensing function of implant 92,relative amplitudes or variations and declinations in contemplated areasof use of the instant system will have no particular effect with respectto the use of this earth involved magnetic field.

For the instant application, magnetometer assemblies as at 104 andassociated probes or pick-ups 106 are configured in the manner offluxgate sensors. The basic fluxgate sensor principal is schematicallyillustrated in connection with FIG. 6. Looking momentarily to thatfigure, the soft magnetic material of a sensor core 120 is periodicallysaturated in both polarities by an ac excitation field evolved from asource 122 which is produced by the excitation current lexc through anexcitation coil 124. In consequence, the core permeability changes andthe dc flux associated with the measured dc magnetic field, Bo ismodulated, the “gating” of the flux that occurs when the core issaturated evolving the term describing the sensor. The device output isusually the voltage, Vind induced into the sensing (pick-up) coil at thesecond and higher harmonics of the excitation frequency. This voltage isproportional to the magnetic field.

Concerning the earth's magnetic field with which the instant embodimentperforms, it may be recalled that earth has a crust, a metal and ametallic core. The inner part of that core is solid and complexprocesses are associated with the increase of the inner core togetherwith the earth's rotational drive, the earth's so-called magnetic dynamowhich is believed to cause the earth's magnetic field. That field has adipole character with a north magnetic pole displaced from thegeographical north pole by about 1000 km. That pole, paradoxically, is asouth pole of an equivalent bar magnet, inasmuch as it attracts thenorth pole of a magnet needle. The earth's field is changing in time,for example, the amplitude is decreasing by 0.1% each year and the poleis drifting westward by 0.10 per year. The tilt of the dipole axis isdecreasing by 0.20 per year.

A magnetometer which may be employed to carry out the functions ofmagnetometer assembly 104 and associated probe or pick-up 106 may beprovided, for example, as a multipurpose precision magnetometeridentified as a type (MPN) 4.0 marketed by Walker LDJ Scientific, Inc.of Troy, Mich. For a further discourse concerning magnetic sensors andmagnetometers, reference is made to the following publication:

-   -   (39) Magnetic Sensors and Magnetometers, edited by P. Ripka,        Artech House, Inc., Norwood, Mass., pp 75-127, 380-391 (2001).

To carry out temperature sensing using the soft ferrite sensors havingpermeability/temperature characteristics as represented at curve 42(FIG. 2) the flux lines of the relatively low flux intensity field whichencounters the sensors are evaluated for perturbance in an intermittentfashion. More particularly this Curie point based temperature monitoringoccurs only during an interrogation interval during which ACF assembly94 is in an off-state and magnetometer assembly 104 is enabled. Forinstance, the ACF heating assembly 94 is enabled for about 100milliseconds to about 1000 milliseconds (ms) and the magnetometerassembly 104 then is enabled for a sequential 10 ms to about 100 ms.This provides an almost continuous noise-free monitoring and the offinterval for the ACF heating assembly 94 permits a modicum ofaccommodation for thermal inertia resulting “overshoot” which may beencountered within the heating components of implants as at 92 as theyreach target temperature or Curie transition temperature. With theinstant system, the duty cycles of these functions can be established bythe operator or may be preset at time of manufacture of the controlsystem.

A graphic illustration of the performance of the ACF heating function 94and magnetometer function 104 is provided in connection with FIG. 7.Referring momentarily to that figure, it may be noted that the graph issectioned in terms of time along its abscissa, while power applied tothe heater components or tissue is represented along a left ordinate.Illustrated as a rightward ordinate is the temperature of the implantedsensor and the relative permeability of that sensor corresponding withsuch temperature. The noted power is seen to be identified alongordinate 130 as extending in value essentially from zero to appliedpower P_(a); temperature of the implanted sensor is shown at ordinate132 extending from body temperature, T_(body) to a setpointcorresponding with Curie temperature, T_(SP); and the relatedpermeability of the implanted sensor is represented along ordinate 134as extending from μ_(MIN) (unity value for relative permeability) andextends to generally starting relative permeability which may fallwithin a substantial range, for example, to values of about 100 to10,000. A maximum relative permeability level for the given sensor athand is represented at dotted horizontal line 136, while the relativepermeability of the ferromagnetic sensor component employed with theimplant or as the implant is represented at dashed curve 138. Set-pointtemperature, T_(SP), is represented at the horizontal dashed line 142and the gradually increasing temperature of the implant heatercomponent, which influences the temperature elevation of involved tissueis represented by dashed line 144. Because of the proximity of thesensor implant with discrete heater components, the temperatures ofthose two components generally will be substantially equal. The level ofpower applied, P_(a) is represented by the dashed line 146 whichinitially exhibits a horizontal orientation.

Now considering the intermittent activation or duty cycle-definedapplication of power and enablement of sensing features, it may beobserved that power is represented as initially being applied as shownat power curve 148 between times t₀ and t₁, representing a powerapplication increment of time ^(δ)t₁. Following this power applicationinterval, ACF heating function 94 is turned off for a sensing orinterrogation interval extending between times t₁, t₂, representing anincrement of measurement time, ^(δ)t₂. Note that during the intervals,^(δ)t₁ and ^(δ)t₂, the temperature value of the implanted sensor asindexed along ordinate 132 and shown at dashed curve 144 commences torise and is seen to exhibit a modicum of thermal inertia duringinterrogation interval ^(δ)t₂. This power-on-power-off-interrogationsequence continues, for example, a power-on condition being appliedbetween times t₂ and t₃ with an interrogation interval occurring betweentimes t₃ and t₄. As these power-on and sensing or interrogationintermitting cycles continue, curve 144 is seen to rise, eventuallyapproaching the setpoint temperature T_(SP). For illustrativeconvenience, note that the figure is broken following time, t₅. Setpointtemperature at line 142 is shown being acquired during the heatinginterval t_(n) to t_(n+1). At the termination of that power applicationtime interval, t_(n+1), Curie temperature is achieved with a slightthermal overshoot as represented at point 150 of curve 144. Note, asthis occurs, that a permeability curve 138 knee 152 change of state isexperienced and the relative permeability of the implanted sensorcomponent drops dramatically, essentially to a unity value asrepresented at curve 138 inflexion point 154 occurring at time t_(n+2).Under the ensuing time element, until the temperature of the sensingcomponent drops, for example, as represented at temperature dropidentification, ΔT_(S) at point 156 of curve 144, relative permeabilitywill remain at the unity level 158 of curve 138. This unity level 158will continue until a sufficient temperature drop excursion at theimplanted sensor component is experienced, whereupon, as represented byknee 160 in curve 138, relative permeability then abruptly rises, asrepresented at curve portion 162, to reassume a high relativepermeability, μ_(N) at time t_(n+3) and as illustrated at the knee of164 of curve 138. With a magnetic disturbance now being detectable bythe magnetometer function 104 and probe or pick-up 106, at the nexttimed heating increment at time t_(n+4), power again is applied for afixed interval of heat application and the result is illustrated bycurve 144 at region 166 showing a positive temperature slope extendingto a slight thermal over-shoot at time t_(n+5), a time condition whereinthe sharp knee 168 of a Curie transition is witnessed at curve 138 toevoke a sharp drop in relative permeability as represented by curveportion 170. This fluctuating activity evokes the noted binary form ofsensory response wherein magnetic field disturbance essentially isstopped and the disturbance termination is detected through pick-up 106by magnetometer 104. As represented by sensor/tissue temperature curve144 at region 172, the sensor/heater/tissue temperature then dwells inlower adjacency with the temperature setpoint T_(SP) until thepre-model-based election of heat application interval is completed todefine a thermal energy quantum of treatment to the given target tissuevolume. It may be recalled that the Curie transition evoking this binarycontrol of heat application is quite accurate, being within about 0.1°C. and 1° C. for a typical application.

If the power setting for the ACF heating assembly 94 is set-only to alevel which eventually will reach the setpoint, T_(SP), sometimesreferred to as a saturation level, then as the temperature curve 144approaches the setpoint level, power will be on, for example, about 90%of the time. However, for typical applications, the power will be morethan twice that saturation level in view of differences in the effect ofthe quantum of thermal energy applied. In the latter regard, vascularityin the region of the target tissue and the nature of that tissue itselfwill influence the effectiveness of the thermal energy introduction. Ofcourse, this power level can be backed off as the tissue or sensordetected temperature reaches or approaches the setpoint value to avoidan overshoot or excessive overshoot.

Recalling the commentary provided in connection with the criticaltemperature curve 24 of FIG. 3, a form of proportional control iscontemplated in addition to the intermitting approach of application ofconstant power followed by a quiescent measurement period. In thisregard, increments of thermal energy for longer intervals can beemployed at the commencement of development of a quantum of thermalenergy and those increments can be diminished as the temperaturesetpoint is asymptotically reached as illustrated in connection withregions 156, 166 and 172 at curve 144.

Returning to FIG. 5, the user interactive functions of the controlconsole 112 are addressed. Applied power levels are set by the user inconjunction with the apparatus 94 itself or may be preset at the time ofmanufacturer of apparatus. However, the control console then looks to atiming parameter for correctly establishing the energy quantum ofthermotherapeutic application.

The control represented at console 112 is powered-on with a key switch180, such a power-on condition being represented by the illumination ofa green LED 182. While typically established by the manufacturer of thecontrol 112, the duty cycles for the application of power or heat andthe quiescent interval immediately following such heat application areshown as being electable by the user. Insertion of this operationalcriteria is provided at the switch combination shown generally at 184.The switches 184 include a heat interval input 186 and a correspondingsensor interrogation interval adjustment function 188. See the timeinterval ranges for ^(δ)t₁ and ^(δ)t₂ set forth in Table 1. With theduty cycles established, next, the timing aspects of the procedure areaddressed in conjunction with a “Therapy Times” user input. Two timesare set by the user, a therapy duration (TD) commencing with theattainment of setpoint temperature T_(SP). and a maximum time to reachsetpoint temperature (TTT_(SP)). Insertion of these times into thecontrol 112 is carried out using up/down switches represented generallyat 190 in conjunction with switch display 192 providing a visuallyperceptible visual time selection, for example, in minutes. Electionbetween the setting of therapy duration (TD) and maximum time tosetpoint temperature (TTT_(SP)) is made by throwing toggle switch 191between its two election orientations.

The platform 52 or corresponding chair assemblage for supporting thepatient 50 is adjusted for its motion parameters, particularly that oftravel distance. It may be recalled that, in general, this travel mayextend to as much as about 10 cm. The frequency of that travelpreferably is pre-established by the manufacturer of the system.However, if desired, adjustment can be provided in conjunction with thecontrol console 112. However, the extent of movement of platform 52along a linear locus is established by up/down switches representedgenerally at 194 which are actuated in conjunction with observation of adigital display readout provided in centimeters as illustrated at 196.Oscillatory drive is initiated for the platform 52 by actuating themotor control circuit 78 via momentary on switch 198. Actuation ofswitch 198 will, in turn, cause the illumination of a green LED 200. Theoperator can stop this oscillation of platform 52 by actuation ofmomentary off switch 202.

In the course of setting up a therapy, certain associatedinterconnections will be made by the operator. The control systemrepresented by the console 112 will respond to errors in that set-upprocedure and provide visual cues as to the error involved andadditionally will provide a prompt as to corrective action to be taken.That information is provided at a visual display 204. Display 204 alsowill provide a display of pertinent data concerning a completed therapyby operator actuation of momentary on-switch 206. That data also will berecorded automatically in data log memory.

During the course of setup and subsequent therapeutic operation of thesystem, an array of visual indicators as to the progress of theprocedure as represented generally at 208 will provide confirmationaloutputs. In this regard, a table/chair ready indication is provided byillumination of green LED 210. The motor control 78 is configured with amotor status comparator which provides an on or enabled condition wherethe voltage of the motor control system exceeds or equals, for example,3 volts. Next, the illumination of a green LED 211 indicates that an ACFheating assembly 94 switch located at that unit has been thrown to applypower. Additionally, it's illumination indicates that the magnetometercontrol 104 monitoring features have indicated that peak-to-peakvariations of its control voltages are greater than a reference value.

LED 212, when illuminated, provides for an indication that magnetometer104 is in a ready condition. In this regard, its power-on switch willhave been actuated to an on condition and its peak-to-peak drive voltagewill have equaled or exceeded a reference voltage value. Next, green LED213 is illuminated to provide an indication that therapy is in progress,and green LED 214, when illuminated, indicates that the therapy durationhas now been reached and therapy is completed. Finally, green LED 215 isilluminated to indicate that the target temperature or setpointtemperature, T_(SP) (FIG. 7) has been reached. Once setpoint temperatureis reached, this LED 215 will remain illuminated until the end of thetherapy or until the stopping of the therapy.

Therapy is commenced with the user actuation of the momentary on starttherapy switch 220. During the interval of the therapy, the elapsed timeof therapy is indicated at display 222. That display may be reset tozero by actuation of momentary on switch 224. If, during the progress oftherapeutic performance by the system, the operator deems it advisableto stop the therapy, then the stop therapy switch 226 is momentarilyactuated and the therapy stopped red LED 228 is illuminated.

Concerning the general operation of the control function 112, it may benoted that unless the checking logic of the control system will havefunctioned to carry out the illumination of the “ready” LEDs 210-212,then the start therapy switch 220 will not be enabled. In general, errorand prompt messages will remain at the display 204 where these startupconditions are not satisfied.

Referring to FIGS. 8A and 8B, which should be considered in connectionwith the labeling shown thereon, a more detailed representation of thesystem at hand is revealed. For the embodiment thus far described, theearth's magnetic field is employed in conjunction with the sensingaspects of the system. That magnetic field is represented in block format 234 in adjacency with the patient support function represented inblock form with the earlier numerical identification 54. In adjacencywith the patient support function 54 there is shown the ACF heating coilor antenna represented in block form again with the number 98. Themagnetometer pick-up 106, is similarly shown in block form with the sameidentifying numeration. Heater coil or antenna 98 again is representedas being coupled with the ACF heating assembly 94 via cable 100 and thepick-up 106 is shown associated with magnetometer control 104 inconjunction with earlier described cable 108 carrying the inducedperturbation voltage V_(ind) (FIG. 6). The patient drive support earlierdescribed at 64 is represented in the instant figure in block form andits mechanical drive association with the patient support function 54 isrepresented by dashed line 236. Patient support drive function 54 againis shown in interactive communication with a motor control circuitrepresented at block 78. In addition to providing for a control over theextent of the locus of travel of the platform 52 and the frequency andrelated rate of its oscillation, the motor control 78 functions to carryout an enablement check as earlier described wherein its actuatingcircuit is tested for the presence of a confirming minimum voltage,V_(MC) which will be greater than or equal to, for example, three volts.That data and assertion of the status check is sequentially controlledas represented by dual arrow 238 from a controller represented at block240. Controller 240 may be implemented, for instance, as a programmablelogic device (PLD) or may provide microprocessor-driven logic controlover the system. Line input to the motor control 78 again is representedat arrow 82. Similarly, arrow 110 shows line input to magnetometercontrol 104 and arrow 96 shows such line input to the ACF heatingassembly 94. Motor control 78 functions to actuate the motor drivenpatient support drive 64 initially upon the actuation of start switch198 as represented by dual arrows 242 and 244. These arrows extend tostart switch 198 as reproduced in block form herein. Similarly, a stopcommand is provided from stop switch 202, again represented in blockform in the instant figure. The stop command is shown presented fromdual arrow 242. The initial table ready status LED, as represented inblock form with the earlier notation 210, is caused to be illuminated,when appropriate, in consequence of the status signals provided at line238 to controller 240 and by virtue of input from the latter controller240 thereto as represented at dual arrow 246. A similar energization ofthe presence of table oscillation LED 200 is provided from a statusinput via line 238 from motor controller 78 to controller 240 andconsequent energization of the LED 200 as represented by dual arrow 248.

Magnetometer assembly 104 control is enabled from acomparator/discriminator circuit represented at block 250, theinteractive relationship being represented in general by the arrow pair252. Upon powering up of magnetometer assembly 104, the comparatorcarries out a determination as to whether its peak-to-peak drive voltageexcursions V_(MO) are equal to or exceed a reference voltage V_(FM).That reference voltage is provided by a reference network represented atblock 254 and arrow 256. Where that test is met, then an enable signalis provided to controller 240 as represented by arrow 258. Thecontroller 240 additionally transmits start and stop commands to thecircuit 250 as represented at arrow 260. The locus of travel distancesupplied by the operator from up/down switch 194 is submitted tocontroller 240 as represented at arrow 243 while the correspondingdisplay of the elected travel extent represented at corresponding block196 is applied from controller 240 as represented at arrow 245. Thatinformation is supplied to the motor control function at block 78 asrepresented at dual arrow 238.

Where multiple implants, for example, combining a heater component and asensor component are positioned within the target tissue volume, theymay be identified, inter alia, by orientation as well as position. Inthe former regard, where the implants have a predominate lengthwisedimension, i.e., wherein their aspect ratio is less than unity, thentheir orientational aspect with respect to an impinging magnetic fieldwill result in an alteration of the resultant perturbance-relatedamplitude detected by the magnetometer assembly 104. By submitting suchamplitude data to a discriminator or window function, the location ofthese implant sensors can be confirmed. Under circumstances where it isdesirable to utilize sensor implants exhibiting different temperaturesetpoints, the acquisition of these differing setpoint temperatures maybe detected in correspondence with magnetometer output signalamplitudes, i.e., as signals representing lower temperatures and theirassociated amplitudes disappear, signals exhibiting a differentamplitude representing a higher setpoint temperature will persist.Accordingly, threshold data can be supplied to the controller 240 fromthe comparator/discriminator function 250 as represented by arrow 262.Where the peak output, V_(MO) satisfies the requirement of referencevoltage 254, then the comparator 250 also provides an enable signalvoltage V_(C.), as represented at arrow 264, to the comparator network266 operationally associated with the ACF heating assembly 94.

Returning to controller 240, an enablement of the magnetometer controlprovides for the energization of the magnetometer ready LED 212 asrepresented at arrow 268. Binary signals representing the acquisition ofCurie temperature are provided from the network 250 and magnetometercontrol 104 to the controller function 240 as represented at arrow 270.This, in turn, provides for the controller 240 energization of thetarget temperature reached LED 215 as represented at arrow 272 andcorresponding block 215 as well as the commencement of time-out oftherapy duration. Operator inputted or manufacturer established dutycycle data and, particularly, the interrogation interval input switchfunction 188 of switch grouping 184 is asserted to the controller asrepresented at arrow 274 extending from corresponding block 188.

ACF heating assembly 94 performs only upon the satisfaction of a triadof preliminary conditions. Initially, the enablement of the magnetometercontrol signal, V_(C) as presented at line 264 must be present andverified as being greater than a reference voltage value, Z as derivedfrom a reference network represented at block 280 and arrow 282. Thiscomparison is provided at a comparator network represented at block 266.Next, the comparator network 266 determines a closure of ACF activationswitch by determining that the corresponding signal, V_(RF) is above areference value, Y. Finally, the comparator determines the presence of astart therapy switch 220 activation by observing a resultant voltageoutput generation V_(T) as being greater than reference voltage value,X. Upon the occurrence of these three enablement conditions, anenablement input is provided to controller 240 as represented at arrow286. Inputs from the ACF heating apparatus 94 are provided to thecomparator function 284 as represented at arrow 288 and a comparatorverified on and off input to the ACF heating assembly 94 is providedfrom the controller 240 as represented at arrow 290.

Controller 240 responds with respect to the actuation of power on/offswitch 180 as represented at arrow 292; responds to the start therapyswitch 220 as represented at arrow 294; and responds to the stop therapyswitch 226 actuation as represented at arrow 296. Heating interval,^(δ)t₁ information as provided either by the manufacturer or from switch186 is supplied to the controller 240 as represented at arrow 298.Controller 240 responds to the above-noted actuation of on/off switch180 as represented at arrow 292 to energize the on LED 182 asrepresented at arrow 300.

A timing network as represented at block 304 performs in concert withthe controller function 240 as represented by dual arrow 306. Network304 responds to the time selections from duration up/down switch 190 asrepresented at arrow 308, as well as to a reset input from the resetswitch 224 as represented at arrow 310. That reset signal additionallyis submitted to the controller 240 as represented by arrows 310 and 312.The output of time election switch 191 is submitted to the controller240 as represented at arrow 309. Elected time data is supplied from thecontroller 240 to the display 192 as represented at arrow 314 and thetherapy time elapsed data as retrieved from timing network 304 issupplied by the controller 240 to the therapy time elapsed display 222as represented at arrow 316. Therapy in progress LED 213 is controlledfrom controller 240 as represented by arrow 322. The completion oftherapy as is derived from timing network 304 is responded to bycontroller 240 to energize the therapy completed green LED 214 asrepresented at arrow 318. Correspondingly, the stop therapy input fromswitch 226 is asserted to controller 240 as represented at arrow 296.This provides for a corresponding reaction to energize the therapystopped red LED 228 as represented at arrow 320. For safety purposes,the output of the stop therapy switch 226 also is simultaneouslysubmitted to the ACF heating assembly 94 as represented by arrow 297.

The error, prompt and data display 204 is reproduced in the instantfigure in block form with the same identifying numeration in conjunctionwith a display driver represented at block 324. Operative associationbetween driver 324 and display 204 is represented at arrow 326 and thecorresponding operational association between controller 240 and driver324 is represented at arrow 328. By operator actuation of the displaydata switch 206, as represented at communications arrow 330, controller240 reacts to provide corresponding visual data at display 204.Controller 240 also maintains a memory based data log as represented atarrow 332 and block 334. The data log retained data, of course, can bedownloaded to paper or magnetic records. Power supply for requisitecomponents of the control circuitry is represented at block 336 inconjunction with line input arrow 338 and regulated d.c. circuit powerinput as represented by an arrow array shown generally at 340.

The discourse now turns to discussion of the implanted sensor componentsas they may be intimately combined with implanted heater components orperform separately with or without such heater components. In an initialembodiment, the implant assumes a cylindrical form of dimensioneffective for implantation within a target tissue volume. In thisregard, its configuration and dimensions should be suitable, forexample, for percutaneous placement by utilizing a modified version of ahypodermic syringe. Thus, a minimally invasive implantation scheme isavailable to the practitioner. Looking to FIG. 9, the general shape of acombined sensor and heater implant 350 is shown with a cylindricalconfiguration. It may be noted that its length exceeds its diametricextent such that it will exhibit an aspect ratio of height or diametricextent divided by length of less than unity. This aspect ratio permitsestablishing an inclination with respect to encountered magnetic fluxpaths so as to provide an amplitude defined position or Curie transitiontemperature signature for a magnetometer readout. The operational anddimensional aspects of the implants described herein are summarized inTable 1.

Looking to FIG. 10, the implant 350 is seen to have a length, L₁ whichwill range, for example, from a minimum value of about 0.05 inch (1.3mm) to about 4.0 inch (102 mm) and a preferred length range of fromabout 0.10 inch (2.5 mm) to about 2.0 inch (51 mm). The diametricextent, D₁ of implants 350 range from about 0.01 inch (0.25 mm) to about0.50 inch (12.7 mm) and will fall within a preferred range of from about0.02 inch (0.51 mm) to about 0.20 inch (5.08 mm). Note that implant 350is shown in FIG. 10 to be formed of two right semi-cylindricalcomponents, a sensor component 352 and a heater component 354.Components 352 and 354 are intimately joined together along their commonflat boundary surfaces with a bonding agent 356. Thermal resistance,TRI, between the heater and sensor will be about 50 C/watt andpreferably (TR2) about 0.5° C./watt. As discussed in conjunction withFIG. 2 above, the sensor component 352 is formed with a ferromagneticmaterial having a formulation exhibiting a Curie temperature basedpermeability transition of interest which exhibits an abrupt change inmagnetic permeability, i.e., about a 20 to 1000 fold change over arelatively narrow range, for example, from about 0.1° C. to about 1° C.Recalling curve portion 156 in FIG. 7, ΔT_(s), the sensor temperaturerange about setpoint temperature T_(SP) will be in a range extendingfrom about 0.1° C. to about 10° C. and, preferably in a range extendingfrom about 0.1° C. to about 3° C. The sensor component 352 is intimatelycoupled through the bonding agent 356 to the heater component 354 which,in turn, is a non-magnetic inductively energizable device formed, forexample, of an austenitic stainless steel such as Type 316, titanium andtitanium alloys and nitinol. The heater component 354 will exhibit aheater temperature range, ATheater about the setpoint, T_(SP) (FIG. 7)of from about 0.1° C. to about 20° C. and preferably from about 0.1° C.to about 3° C. This will provide or develop a tissue temperature rangeabout the setpoint T_(SP), ΔT_(t) from about 0.1° C. to about 8° C. andpreferably in a range between about 0.1° C. and 3° C. Looking to FIG.11, the semi-cylindrical diameters or heights of the sensor 352 andheater 354, are respectively indicated as H₁ and H₂. Those heights willfall within a range of from about 0.005 inch (0.13 mm) to about 0.25inch (6.4 mm) and preferably within a range of from about 0.01 inch(0.25 mm) to about 0.10 inch (2.5 mm). Bonding agent 356 may be providedas adhesive such as a cyanoacrylate, acrylic or an epoxy adhesive, or abonding agent such as a solder or a braze. In general, the adhesive orbonding agent will exhibit a thickness, t₇ of between about 0.0001 inch(0.0025 mm) and about 0.03 inch (0.75 mm) and, preferably, between about0.001 inch (0.025 mm) and 0.015 inch (0.38 mm) and will establish theabove-noted thermal resistance. The good thermal communication betweenthe heater 354 and sensor 352 provides for desirable maintenance of theheater component 354 at temperatures close to the correspondingtemperature of the sensor 352 as it is elevated toward a Curietransition temperature. The outer surface of the implant 350 may becovered with a biocompatible coating shown in the FIGS. 10-13 at 358.Coating 358 may be provided as a Parylene C (poly monochloro-p-xylylene)coating of thickness, t₂ ranging from about 0.001 inch (0.0025 mm) toabout 0.010 inch (0.254 mm) and preferably between about 0.001 inch(0.025 mm) and about 0.003 inch (0.076 mm). Such coatings are availablefrom organizations, such as Specialty Coating Systems, of Indianapolis,Ind.

Once implants as at 350 are accurately positioned within or in adjacencywith targeted tissue, it is desirable that they remain in place. Thisfollows, inasmuch as hyperthermia therapy typically will be repeated atgiven intervals for a multi-application treatment regimen.Advantageously re-implantation is not necessary. Of further benefit,typical surgical or biopsy procedures, for example, involving the breastcall for the implantation of a radiographic marker. These markers areemployed in subsequently occurring patient management procedures. Theinstant implants contribute the same radio-opaque marker function insubsequent patient management practice.

Referring to FIG. 9A, implant 350 reappears with its mutually bondedsemi-cylindrical sensor component 352 and heater component 354. Notethat mutually oppositely inwardly disposed tissue engagement implementsin the form of barb-like projections 353 a and 353 b are fixed to andresiliently extend from heater component 354. When implant 350 isreleased into target tissue by an implantation instrument, (FIGS. 32 and33), the implements 353 a and 353 b will spring outwardly intoengagement with adjacent tissue. Connection of the implements 353 a and353 b to implant 350 is facilitated by coupling with heater component354. In this regard, connection may be carried out by welding orforming.

FIGS. 12 and 13 reveal an adaptation of the implant 350 wherein it isemployable not only for the purpose of thermotherapy, and in particularhyperthermia applications, but it also carries a thermally activatablerelease agent coating shown at 360 to provide an adjunct therapy. Bycontrolling or regulating such release with respect to the accuratetemperatures made available with the instant system, multiple dosages ofa release agent based therapeutic program may be achieved by theactivation of the heating component 354 under the sensor 352 basedcontrol of the system at hand. Exemplary of such thermally activatablerelease agent coatings as may be provided at 360 are liposome andcapsulated anti-tumor drugs as described in the following publication:

-   -   (40) Kong, G., et al., “Efficacy of Liposomes and Hyperthermia        in Human Tumor Xenograft Model: Importance of Trigger Drug        Release.” Cancer Research, 60 (24): 6950-6957 (2000).

Another exemplary release agent coating includes atemperature-responsive polymeric micelle prepared using block copolymersof poly (N-isopropylacrylamide-b-butylmethacrylate) as discussed inpublication (9) supra.

In one arrangement of this release agent embodiment, the thermallyactivated release agent coating is formulated to provide a controlledrate of release of an anti-tumor when the heater/sensor implant 350reaches its pre-selected therapy temperature, for example, thetemperature setpoint, T_(SP), as discussed in connection with FIG. 7.The thickness of, t₃, of the thermally activatable release agent coating360 may, for example, range from about 0.001 inch (0.025 mm) to about0.20 inch (5.1 mm) and preferably between about 0.005 inch (0.13 mm) andabout 0.10 inch (2.5 mm). Nominal release agent temperature (T_(DRS))ranges will extend from about 39° C. to about 65° C. and preferably fromabout 41° C. to about 50° C.

The ferromagnetic sensing components of implants as at 350 generally arefabricated utilizing molded pressed powder technology. As such, theygenerally will exhibit adequate compressional strength but somewhatlower tensile strength. Thus, where they are incorporated in an embeddedor clad heater/sensor combination it is preferred that the sensorcomponent be internally disposed. However, it is essential that thesurface of the sensor be exposed somewhat for appropriate reaction tothe impinging magnetic field. Conversely, it is important that thesurface of the heater component be readily exposed to, for example,E-field imposed activity to achieve requisite temperature development.

An embodiment for a heater/sensor implant structured having an outwardlydisposed heater sleeve is shown in FIGS. 14-16 in general at 370. Asrepresented in those figures, the implant 370 is configured having aninternally disposed cylindrical sensor component 372 fashioned with thematerial as described in connection with sensor component 352 (supra).Cylindrical sensor component 372 is seen in FIG. 15 to have an outersurface 374 disposed along a central axis 373. Over the outercylindrical surface 374 (FIGS. 15, 16) of component 372 there ispositioned a heater component 376 formed of the material described inconnection with heater component 354 (supra). Note in FIG. 14, however,that the heater component 376 is fashioned as a perforated sleeve whichsurrounds and is in good thermal communication with the cylindricalsensor component 372. Formed with a plurality of openings, certain ofwhich are identified at 378, the sleeve-configured heater component 376thus provides magnetic field access to the surface of sensor component372, while being in intimate contact with adjacent tissue for heattransfer purposes and for response to inductively imposed E-fields.Openings 378 are seen to be arranged in a regular pattern, for theinstant embodiment, of somewhat rectangular periphery. In this regard,FIG. 14 reveals that the openings 378 are configured with a height W₆and a height-to-height inter opening spacing, W₇. FIG. 15 identifies awidth dimension, W₂ for the openings 378 and a width-to-width spacing,W₁ for those openings. Additionally, the figure reveals that thesleeve-shaped heater component 376 exhibits a radial thickness, t₁. Forthe present embodiment, the cylindrical outer surface 374 of the sensorcomponent 372 is coated with a biocompatible conformal coating 380.Biocompatible coating 380 may be provided in the same manner as coating358 (supra) with thicknesses, t₂. A manufacturing approach for formingthe implant 370 is to form the developed structure of the heater 376into a cylinder by rolling, whereupon a welding step will complete theheater as a cylinder with a longitudinal seam. That perforate cylinderthen is mounted upon the corresponding cylindrical sensor 372. It shouldbe borne in mind that the conformal coating 380 described above can beapplied over the combined heater and sensor implant assembly. Thisconformal coating, in addition to providing a very thin electricallyinsulative surface, additionally has been found functional as aneffective adhesive joining medium.

As before, the alphanumerically identified dimensions and operationalattributes are compiled in Table 1. Heater segment width, W₁ will bewithin a range from about 0.005 inch (0.13 mm) to about 0.25 inch (6.3mm) and preferably within a range from about 0.010 inch (0.25 mm) toabout 0.10 inch (2.5 mm). The distance between heater segments, W₂ willbe within the same dimensioned ranges or dimension W₁. Further, thetabulated ranges for ΔTheater and ΔT sensor continues to be applicableas well as the values for thermal resistance, TR1 and TR2.

As discussed in connection with FIG. 9, re-installment of the implants370 is not required for a succession of hyperthermia treatments, and theinstant implants offer the added benefit of serving as radiographicmarkers for subsequent patient management practices.

Referring to FIG. 14A, implant 370 reappears with its mutually bondedcylindrical sensor component 372 and overlayed heater component 376.Note that heater component 376 is configured having resilient,integrally formed and outwardly extending tissue engagement implementsin the form of barb-like projections 377 a and 377 b. When implant 370is released into target tissue by an implantation instrument (FIGS. 32and 33), the implements 377 a and 377 b will spring outwardly intoengagement with adjacent tissue. This feature, combined with theperforate surface of implant 370 functions to avoid implant migrationover an interval of successive therapy sessions, and subsequent patientmanagement procedures.

Another embodiment for a combined sensor and heater implant is revealedin connection with FIGS. 19-21. Referring to FIG. 19, an implantrepresented generally at 384 is seen to have a sensor component 386, thesurface 388 of which extends along axis 390 to define a rightcylindrical configuration. As represented in FIGS. 20 and 21, thatsurface 388 may be coated with a biocompatible electrically insulativeconformal coating 392 such as the “Parlyene” product described abovehaving the noted thickness, t₂. The Curie transition temperatureresponsive sensor 386 is conjoined with a heater component representedgenerally at 394. Component 394 is formed as a continuous, generallyopen, helical or spiral sleeve herein configured as a band which ispositioned in thermal exchange relationship about the cylindrical sensorsurface 388. This intimate thermal exchange relationship between theheater component 394 and the sensor component 386 is revealed in FIG.21. In general, the open spacing between the helically wound bandcomponents will have the earlier described spacing value W₂ and a bandwidth corresponding with the earlier-described value W₁. Cylindricalsensor component 386 will have a diameter D₁ and a length L1 asearlier-described. Helically-shaped heater band 394 may be configured inthe form of a helical spring formed either of flat wire construction inthe manner shown in the instant figure or of wire of generally roundcross-sectional configuration. In general, the helical heater componentband 394, whether formed as a round spring or as a helical structure ofrectangular cross-section as shown will be wound so that its insidediameter is slightly less than the outside diameter of the sensorsurface 388 with or without the biocompatible conformal coating 392. Forthe assembly process, by temporarily partially unwinding the helicalheater 394, its inside diameter will slightly increase such that it canbe positioned securely over the sensor 386. As before, the electricallyinsulative conformal coating such as “Parlyene” may be applied withthickness, t₂, over the assembly of both heater 394 and sensor 386.Additionally, as before, at least the heater component and, morelogically, the entire implant 384 may support a thermally activatablerelease agent coating effective to release an agent at the situs of thetarget tissue in conjunction with the heater component 394 achieving aninduced temperature below or generally corresponding with the Curietransition temperature, T_(c). The tabulated range for ΔT heater and ΔTsensor continue to be applicable to this embodiment, as well as thevalues for thermal resistance, TR1 and TR2. As discussed in connectionwith FIGS. 9 and 14 re-installment of the implants 384 is not requiredfor a succession of hyperthermia treatments. An added benefit further isrealized by subsequent utilization of the implants as radiographicmarkers in patient management procedures. For such procedures as well asfor the initial succession of hyperthermia therapy successions,avoidance of implant migration from position is desired.

Referring to FIG. 19A, implant 384 reappears at 384□′ with its mutuallybonded cylindrical sensor component 386 and surface mounted heatercomponent 394. Note that heater component 386 is configured havingresilient, integrally formed and outwardly extending tissue engagementimplements in the form of barb-like projections 396 a and 396 b. Whenimplant 384 is released into target tissue by an implantation instrument(FIGS. 32 and 33), the implements 396 a and 396 b will move intoengagement with adjacent tissue. This feature, combined with the helicalshaped screw or bolt thread-like surface of implant 384□′ functions toavoid implant migration over an interval of successive therapy sessionsand later patient management procedures.

Looking to FIG. 19B, implant 384 reappears in general at 384□′□′ withcylindrical sensor component 386 and heater component 394. For thisembodiment, the wire-like spiral heater component structure 394 has oneend 394□′ extending outwardly beyond sensor component 386 forming aspirally-shaped tissue engaging implement for migration avoidance. Ofcourse, such engaging implements can extend from either or both ends ofsensor component 386. Turning to FIG. 19C another adaptation of implant384 is represented in general at 384□′□′□′. Again, cylindrical sensorcomponent 386 reappears, but joined with a heater component 396 formedas a screw thread configured somewhat coarsely for anchoring engagementwith tissue. Referring to FIG. 19D, another adaptation of implant 384 isrepresented in general at 384□′□□″□′. Again, cylindrical sensorcomponent 386 reappears. However the heater component as shown at 398 isformed as a sequence of disk-like structures fixed to and extendingoutwardly from the surface 388 of sensor component 386. Implant384□′□′□′□′ is configured for positioning in tissue intraoperatively,i.e., during an open surgical procedure prior to closure, thedisk-shaped heater component structure providing a tissue engagingfunction in avoidance of implant migration.

Referring to FIGS. 22 and 23, another implant embodiment is representedgenerally at 400. Implant 400 is configured having a sensor componentrepresented generally at 402 with a right cylindrical surface 404disposed along an axis 406 between end portions or cylinder ends 408 and410 (FIG. 23). The heater component for implant 400 is comprised of twocap-shaped heater components shown generally at 412 and 414. Each of thecap-shaped components 412 and 414 is formed having a cap end portionshown respectively at 416 and 418. These end portions are shown in FIG.23 to have a thickness t₄.

FIG. 23 reveals that cap end portions 416 and 418 have a thickness t₄,which as tabulated herein will fall within a range of about 0.001 inch(0.025 mm) to about 0.20 inch (5.1 mm) and preferably within a range ofabout 0.003 inch (0.75 mm) to about 0.10 inch (2.5 mm). The cap endportions integrally extend and are formed with cap sleeve portions shownrespectively at 420 and 422. Sleeve portions 420 and 422 will exhibitthe earlier-described range of thicknesses, t₁. Cylindrical sensorcomponent 402 may be coated as represented at coating 424 with anelectrically insulative conformal coating such as the earlier-described“Parylene”. The coating will have the thicknesses earlier-described ast₂. Cap-shaped components 412 and 414 are joined to the cylindricalsensor 404 utilizing a bonding agent 426. That bonding agent may be thesame as that described earlier at 356 in connection with FIGS. 10 and11. With the arrangement shown, a portion of the surface 404 of thesensor component 402 is exposed for interaction with confrontingmagnetic flux. That portion is identified by the cylindrical length orwidthwise dimension W₃. As set forth in Table 1, the exposed length W₃of the sensor component 402 may range from about 0.05 inch (1.3 mm) toabout 4.0 inch (102 mm) and preferably will fall within the range ofabout 0.10 inch (2.5 mm) to about 2.0 inch (5.1 mm). The diameter ofsensor component 402, D₂ as set forth in Table 1, will fall within arange of from about 0.01 inch (0.25 mm) to about 0.50 inch (12.7 mm) andpreferably within a range of from about 0.020 inch (0.51 mm) to about0.20 inch (5.1 mm). The length, L₂, of the overall implant 400 may, asrepresented in the Table, range from about 0.05 inch (1.3 mm) to about4.0 inch (102 mm) and preferably will fall within a range of about 0.10inch (2.5 mm) to about 2.0 inch (51 mm). Table 1 also sets forth rangesfor ΔTheater or heater temperature around the setpoint, ΔT sensor orsensor temperature around the setpoint, P_(heater) or instantaneousheating power generated within the heater, T_(heater) or nominalhyperthermia temperature for the heater component, TRI, the nominalthermal resistance between the heater components and sensor componentsand TR2, the preferred thermal resistance between the heater componentand the sensor component. These tabulated values and ranges of valuesare repeated for each of the embodiments. The heater cap components for412 and 414 as well as the exposed portion of the sensor component 402additionally may support a release agent coating which is thermallyactivatable under or below temperatures corresponding with the Curietransition temperature of the sensor component 402 thus providing anadjunct therapy in addition to the hyperthermal therapy achieved withthe implant or implants as at 400. See the release agent temperatureranges T_(DRS) in Table 1.

Multiple numbers of the sensor components described at 402 may becombined as represented at FIGS. 24-26. Looking to FIG. 24, implant 430is seen to be comprised of sensor components as earlier-described at 402and herein represented having respective surfaces 404 a-404 d extendingalong axis 432. Cap end portions identical to those described at 416 and418 in FIGS. 22 and 23 are provided with the implant 430 as shownrespectively at 416′ and 418′. As illustrated in FIG. 25, these heaterend cap components 416′ and 418′ have the same thickness dimensions, t₄.Retaining the serial assemblage of sensor components 402 a-402 d arethree intermediate heater component sleeves 434-436. Sleeves 434-436 areconfigured with cylindrical outer sleeves shown respectively at 438-440which are integrally formed in connection with innercylindrically-shaped webs shown respectively at 442-444. The cylindricalouter sleeves 438-440 are provided having the earlier discussedthickness, t₁, and are arranged having a width, W₅, of from about 0.02inch (0.51 mm) to about 0.5 inch (12.7 mm) and preferably within a rangeof from about 0.04 inch (1 mm) to about 0.2 inch (5.1 mm). Spacingbetween intermediate heater sleeves 434-436, as well as intermediateheater sleeves as at 434 and heater cap end portion 416′ andintermediate heater sleeve 436 and heater cap end portion 418′ isindicated as W₄. That dimension of exposed sensor length as set forth inTable 1 will range from about 0.05 inch (1.3 mm) to about 4.0 inch (102mm) and preferably within a range of about 0.10 inch (2.5 mm) to about2.0 inch (51 mm). The diametric extent of the sensor components 404a-404 d will fall within the earlier-described ranges of values D₂.Sensor components 402 a-402 d are coupled with respective heater cap endportions 416′ and 418′ utilizing the bonding agent, for example, asdescribed above in connection with FIG. 11 at 356. The bonding agent asrepresented in FIG. 25 at 446 also connects the sensor components 404a-404 d with intermediate heater component sleeves 434-436 asillustrated.

Each of the sensor components 402 a-402 d may be coated with anelectrically insulative conformal coating of thickness, t₂ such as theearlier-described “Parylene” as indicated at 448. This same conformalcoating also may be employed to coat the entire implant 430. As notedearlier, such coatings provide an adhesive coupling contributionsupporting the integrity of the multiple component arrangement. Table 1sets forth ranges for ΔT heater or heater component temperature aroundthe set point, ΔT sensor or sensor component temperature around the setpoint, P_(heater) or instantaneous heating power generated within theheater component, T_(heater) or nominal hyperthermia temperature for theheater component, TR1 the nominal thermal resistance between the heatercomponents and sensor components, and TR2, the preferred thermalresistance between the heater component and the sensor component.

As is the case of all of the implant embodiments, the implant 430 may beutilized to support a thermally activatable release agent coating asshown at 450 in FIG. 26 which is effective to release an agent at thesitus of the target tissue when the heater components 416′, 418′ and434-436 achieve an induced temperature level generally correspondingwith the elected temperature response of the sensor components 402 a-402d which will exhibit a common Curie transition value. The thickness ofthe thermally activated release agent coating 450 in general, willaverage that described in connection with the dimension t₃, asdiscussed, for example, in conjunction with FIG. 12. Table 1 identifiesnominal release agent temperature release ranges, T_(DRS).

As discussed in connection with FIGS. 9, 14 and 19, reinstallment of theimplants 430 is not required for a succession of hyperthermiatreatments. An added benefit further is realized by subsequentutilization of the implants in patient management procedures. For suchprocedures as well as for the initial succession of hyperthermia therapysessions avoidance of implant migration from position is desired.

Referring to FIG. 24A, implant 430 reappears with its linearly assembledcompilation of sensor components 404 a-404 d, heater component sleeves434-436 and heater component end caps now shown in primed fashion at414′□ and 418′□. Note that mutually oppositely inwardly disposed tissueengagement implements in the form of barb-like projections 428 a and 428b are fixed to and resiliently extend from heater component end caps416′□ and 418′□. When implant 430 is released into target tissue by animplantation instrument (FIGS. 32 and 33), the implements 428 a and 428b will spring outwardly into engagement with adjacent tissue. Thediscontinuous nature of the surface of implant 430 also contributes toan engaging relationship with tissue and the combined tissue engagementfeatures serve to avoid implant migration over an interval of successivetherapy successions and later patient management procedures.

In some applications of the instant system, the heating components maybe dispensed with target tissue being, in effect, directly heated fromthe ACF heating assembly 94 and coil or antenna 98 as described inconjunction with FIG. 5 above. Sensor components, exhibiting requisiteCurie temperature transition ranges which are quite narrow are retainedwith the embodiment of the procedure. Contributing to the effectivenessof this technique sans the presence of heater components is that aspectof tumor physiology wherein tumor will absorb heat differentially, i.e.,to a greater extent with respect to normal surrounding healthy tissue.In this regard, while a quantum of thermal energy can be introduced tothe tumor region, the surrounding adjacent normal tissue may bemaintained at lower temperatures primarily due to the vascularity ofthat normal tissue. In the latter regard, the blood supply within normaltissue will have a tendency to remove thermal energy inducedaffectation. Conversely, tumor generally exhibits variational tissuecharacteristics with relatively poor blood profusion and varying butmore enhanced tissue density. (See U.S. Pat. No. 5,099,756).

FIGS. 27-30 look to the utilization of a sensor component only as theimplant 92 as described in conjunction with FIG. 5. That implant then isutilized in conjunction with the heating of tissue at the target tissuevolume from the ACF heating assembly 94 and associated coil or antenna98. Such a sensor-dedicated implant is shown in FIG. 27 in general at454, the implant being shown as a right cylinder, the surface 456thereof being disposed about a centrally disposed axis 458. Implant 454will exhibit the earlier-described desired Curie temperature transitionranges of quite narrow scope and is represented in cross-sectionalformat in FIG. 28. In the latter figure, the implant 454 is seen to becoated with an electrically insulative conformal coating such as“Parylene” as described above and shown at 460. Coating 460 additionallyis shown to exhibit a thickness t₂, the ranges for which have beenearlier described in connection with Table 1. Having a diametric extentof D₁ and a length shown as L₁, the dimensional ranges of which havebeen earlier-described, device 454 functions to monitor the heating of atarget tissue volume as described at 90 in FIG. 5 and to provide thetemperature information necessary to maintain the temperature of thattarget tissue volume within a narrow temperature range, ΔT_(s), aboutthe setpoint for hyperthermia, T_(SP), as described at dashed line 142in connection with FIG. 7. That tissue temperature range about thesetpoint will, for instance, extend from between about 0.1° C. and about5° C. and preferably will fall within a range of from about 0.1° C. and3° C. The implant 454 will exhibit a permeability based state changeCurie transition within the earlier-described narrow range, for example,from about 0.1° C. to about 1° C. Table 1 describes P_(tissue), theinstantaneous heating power generated within tissue, as being within arange from about 0.2 to about 100 calories/second and preferably withina range from about 0.4 to about 25 calories/second.

FIGS. 30 and 31 illustrate an adaptation of the implant 454 wherein itsupports a thermally activatable release agent coating 462. Coating 462may be provided as earlier-described in conjunction with FIG. 12 and isseen to exhibit the earlier-described thickness, t₃, the ranges of whichhave been discussed above and are set forth in Table 1. In addition tothis adjunct release agent therapy, the sensor implant 454, as in theearlier embodiments, may be employed for other adjunct therapiesincluding the induction of heat shock proteins (HSPs). Additionally, theimplant 454 may be utilized as a component of the “triple modality”,radiochemotherapy. See publication (10) supra. The ranges for nominalrelease agent dispersion temperature, T_(DRS) are listed in Table 1.

In general, the implants described in conjunction with FIGS. 9-30 may bepositioned in target tissue utilizing a variation of syringe-hypodermicneedle technology. FIGS. 32 and 33 generally, schematically representone approach to implantation employing such technology. Radiographic,stereotactic, ultrasound or magnetic resonance imaging guidance methodsor palpation are procedurally employed to accurately position an implantwithin a target tissue volume. Of particular interest, the implants maybe positioned intraoperatively as an aspect of open surgical procedures.For instance, a most common approach to the treatment of cancer is thatof tumor excision. Certain cases, for example, involving colorectalcancer will, upon gaining access to the abdominal cavity, reveal asubstantially inoperative metastasis of the disease. Under suchcircumstances the surgical procedure typically is altered to apalliative one, for example, unblocking the colon and/or the incision isclosed and other treatment modalities are considered.

However, with the instant system and method the surgeon is given anopportunity for deploying hyperthermia-based temperature controlimplants by direct access. Of special interest, colorectal cancers tendto metastasize through the lymph system. Accordingly, the implants canbe intraoperatively positioned within lymph nodes to provide for theinduction of HSPs at the node-retained cancer cells. Other sites oftumor similarly can be implanted. Following surgical closure, thehyperthermia therapy procedures described herein can be undertaken inmitigation of the metastasis. In general, practitioners employing themethod herein described with respect to hyperthermia will elect toimplant the most or more accessible target tissue volume.

A target tissue volume is represented in FIGS. 32 and 33 at 470internally within the body 472 of a patient. The syringe-type insertiondevice represented generally at 474 is percutaneously orintraoperatively inserted within the body 472, piercing the skin wherecalled for by virtue of the presence of a sharp tip 476 formed at theend of a needle 478. Needle 478 is fixed to a barrel or finger graspablehousing 480 and removeably retains an elongate implant 482 within itsinternal core proximally from the tip 476. Immediately behind theimplant 482 within the needle 478 is a plunger rod 484, the lower tip ofwhich at 486 is in free abutment against the outwardly disposed end ofimplant 482 and which extends upwardly to a plunger handle 488. As isrevealed, particularly, with respect to FIG. 33, once the sharpened tip476 of the needle 478 has been properly positioned with respect to thetarget tissue volume 470, then a plunger rod 484 and associated handle488 are stabilized positionally with respect to the body 472 and targettissue volume 470, whereupon housing 480 is retracted outwardly to theorientation shown at 480′ in FIG. 33. This maneuver releases implant 482at an appropriate location with respect to the target tissue volume 470.Implantation devices are described, for example, in U.S. Pat. No.6,007,474.

Sensor components having the physical attributes discussed above inconnection with FIGS. 9-31 are formed of soft ferromagnetic materials orsoft ferrites. Ferrites have been considered to be crystalline reactionproducts of the oxides of iron and one or more other bivalent metals orbivalent metallic complexes. The soft magnetic materials are generallycategorized as exhibiting a high inductance, B, for a low field, H.

Particularly for the predominating hyperthermia based proceduresdescribed herein, the soft ferrites are formulated to derive relativelylow Curie point values within, for instance, a range extending fromabout 39° C. to about 65° C. and more typically within a range extendingfrom about 41° C. to about 50° C. Generically, ferromagnetic materialsexhibit pronounced magnetic effects occurring in atoms and ions and stemfrom only a limited number of metallic elements, to wit: Fe, Co, Ni andcertain rare earths. Alloys or oxides of these materials typically willcontain neighboring ions such as Mn to substantially enhance the atomicspin effect. Zn substitution both increases the magnetic moment of Mnand Ni ferrites and lowers the Curie point of a resultant product. Suchsubstitution will be seen to appear in the ferrite formulationsdisclosed herein. The metal ion present in largest concentration inferrites is Fe³⁺. Because of its high ionic moment it has a highpotential for controlling magnetic characteristics. Such effects are notchemical but crystallographic, being related to lattice sitedistribution.

The processes for preparing ferrites have an extensive but relativelyshort history (Snork, D. L., 1936, 1947). Such processes generallyreflect the common goal of formation of a spinel structure. Startingmaterials typically are oxides or precursors of oxides of the cationsand their processing involves an interdiffusion of metal ions of aselect composition to form a mixed crystal. Ferrite powders have beenproduced by precipitation and digestion methods. These powders areblended, calcined and milled and, for the case of spinel ferrites,sintered for a variety of purposes including: (a) completing theinterdiffusion of the component metal ions into a desired crystallattice; (b) establishing appropriate valences for the multi-valent ionsby proper oxygen control; and (c) developing a desired microstructure.During this procedure, the materials are consolidated into a body orcomponent, for example, by die-pressing.

Referring to FIG. 34, a flow chart is presented describing the mostcommonly utilized ceramic process for forming manganese zinc ferrites.As represented at block 471, oxides of the metals are first blended in aratio according to the desired composition, here providing for a desiredCurie point characteristic. The oxides are milled, and as represented atarrow 472 and block 473, the resulting oxide mixture is subjected to athermal treatment called calcining wherein ferrite material issynthesized by a solid state reaction. Generally, this step is performedin air and only a partial ferrite formation is accomplished. Next, asrepresented at arrow 474 and block 475 the calcine material thusobtained is then milled in order to reduce its particle size andhomogenize the material. This step is commonly performed in a steel ballmill. As represented at arrow 476 and block 477 an organic binder isusually added at this stage in order to control subsequent steps ofgranulating or spray drying and pressing. Next, as represented at arrow478 and block 479, in the preliminary stage of the sintering process,the pressed ferrite part is subjected to an oxidizing treatment. The aimof this treatment is to remove the organic binder added previously whichat this stage is burned off by heating the ferrite part in air. Next, asrepresented at arrow 480 and block 481, at a later stage of thesintering process a “soak” is introduced with the aim to restore theoxygen stoichiometry wherein the ferrite part is kept at a hightemperature in an atmosphere deficient in oxygen with respect to that ofthe stoichiometry ferrite.

For the instant system and method, product formulation and processingfurther is called upon to establish Curie points within the abovedesignated range or ranges of values. Customizing ferrites to soestablish a desired Curie point can be carried out, for example, byblending a ferrite exhibiting a Curie transition above the desiredvalue, T_(SP), with one exhibiting a corresponding transition pointbelow that target value.

Recalling curve 42 of FIG. 2, and looking in particular to FIG. 35,curve 484 was derived from a soft ferrite exhibiting a Curie point of44.5° C. The ferrite product was developed utilizing a blendingprocedure wherein a ferrite exhibiting a 120° C. Curie point temperaturewas blended with a ferrite exhibiting a −20° C. Curie point temperature.

The resulting ferrite as represented by curve 484 exhibitedthe-following chemistry:

-   -   Iron 49 wt %    -   Zinc 15 wt %    -   Manganese 9 wt %    -   Oxygen 27 wt %

Further this ferrite represents a formulation of the following oxides:

-   -   Iron Oxide (Fe₂O₃) 51.8 mole %    -   Zinc Oxide (ZnO) 28.1 mole %    -   Manganese Oxide (MnO) 20.1 mole %

Another formulation achieving a 44.5° C. Curie point resulted from acombinational blending, for example, of a 40° C. Curie point batch witha 50° C. Curie point batch.

As a prelude to considering detailed features of the procedure at hand,the discourse now turns to its aspects particularly with respect to heatshock phenomena. Previous research demonstrates that in vitrohyperthermia of cultured tumor cells can act as a vaccine againstmetastatic cancers. Hyperthermia of cultured cancer cells can partiallydenature proteins, induce HSPs, and lead to the presentment ofintracellular peptides on the cell surface. Earlier work has isolatedthe antigen presenting HSPs and used these cell preparations as anautologous vaccine against syngeneic tumors. See:

-   -   (41) Tamura, Y., Peng, P., Liu, K., Daou, M. and Srivastava, P.        K., “Immunotherapy of Tumors with Autologous Tumor-Derived Heat        Shock Protein Preparations.” Science, 278: 117-120 (1997).

The autologous cell vaccine described in Tamura presumably functionsusing heat shock to cause the presentment of intracellular cancer cellantigens. A subset of these cancer cell antigens represent aberrantproteins, and these aberrant proteins can be immunogenic. Once antigensderived from aberrant proteins unique to the cancer cell are presentedto the cells of the immune system, then an immune response can occur. Animmune response raised against aberrant proteins apparently does nottrigger an auto-immune response, since only those cells which aresyngeneic with the cancer cell would be likely to produce the antigenfrom the aberrant protein. An immune response so induced can beeffective against syngeneic cancer cells and can activate the immunesystem against metastatic tumors too small to be otherwise detected.

In the present invention, rather than using invasive surgical techniquesto excise a tumor and then produce a vaccine for that tumor by growingand heat-shocking the tumor in vitro, the tumor is heat shocked in situ,and tumor antigens are presented on the tumor cell surface. Heat-shockcan cause the presentment of novel antigens on the cell surface.Presentment of novel peptides on the cell surface can induceimmunogenicity. A cell which was previously not immunogenic, after heatshock, can thus become immunogenic. For additional background onimmunogenicity induced via a heat-shock mechanism, See:

-   -   (42) Suto, R. & Srivastava, P. K., “A Mechanism for the Specific        Immunogenicity of Heat Shock Protein-Chaperoned Peptides.”        Science, 269: 1585-1588 (1995).    -   (43) Wei., Y.-Q.,Zhao, X., Kariya, Y., Fukata, H., Teshigawara,        K., and Uchida, A., “Induction of Autologous Tumor Killing by        Heat Treatment of Fresh Human Tumor Cells: Involvement of γδ        T-cells and Heat Shock Protein 70.” Cancer Research, 56:        1104-1110 (1996).    -   (44) Yanase, M., et al., “Antitumor Immunity Induction by        Intracellular Hyperthermia Using Magnetite Cationic Liposomes.”        Jpn. J. Cancer Res., 89: 775 (1998).

The present invention offers the advantages of reduction in the invasivenature of the therapy, as a tumor need not be removed from the body ifthe tumor responds to thermotherapy. Moreover, tumors which areotherwise inoperable because present surgical techniques do not allowtheir excision (e.g. certain brain tumors), could not be excised for invitro treatment. By appropriate placement of the instant implant near orwithin targeted tumor, hyperthermia in situ can offer the same benefitsas an autologous vaccine derived from excised, cultured cells.Additional complications caused by surgery and infection potentialcaused by reintroduction of tumor derived products can likewise beavoided.

The present approach also offers the thermal control aspect of beingable to take advantage of different thermotherapy regimes, so that tumorcells, at different occasions can be induced to undergo heat shock,apoptosis or necrosis. A tumor may receive an implant and then besubjected to an initial round of mild thermotherapy, sufficient toinduce only heat shock, but not apoptosis or necrosis. The initialtherapeutic regime may be for a short duration (or at lower temperature,or both) designed to induce to a panel of heat shock proteins induced byonly mild heat shock (e.g. activating HSF1 and HSP70). Referring to FIG.3, the initial round of thermotherapy may be programmed to remain belowthe line 24, so that no irreversible tissue effects would occur. (Anexample of this regime would be a temperature elevation, ΔT=+4° C. for aduration of 45 minutes. This is achieved by selecting a target orsetpoint temperature and therapy duration effective for the induction ofHSP).

For a discussion of induction of the heat shock response following mildheat shock see:

-   -   (45) Morrison, A. J., Rush, S. J., and Brown, I. R., “Heat Shock        Transcription Factors and the hsp70 Induction Response in Brain        and Kidney of the Hyperthermic Rat During Postnatal        Development.” Journal of Neurochemistry, 75: 363-372 (2000).    -   (46) Neiland Thomas J. F., M. C. Agnes A. Tan, Monique        Monnee-van Muijen, Frits Koning, Ada M. Kruisbeek, and Grada M.        van Bleek, “Isolation of an Immunodonminant Viral Peptide that        is Endogenously Bound to Stress Protein gp96/GRP94.” Proc. Nat'l        Acad. Sci. USA, 93: 6135-6139 (1996).    -   (47) Tanabe, M., Nakai, A., Kawazoe, Y., and Nagata, K.        Different Thresholds in the Responses of Two Heat Shock        Transcription Factors, HSF1 and HSF3.” Journal of Biological        Chemistry, 272: 15389-15395 (1997).

It should be noted that different tissues respond at differing rates toheat-shock, for instance brain tissue responds more rapidly than liveror muscle tissue. Though the response curve in FIG. 3 is a compositederived from several empirical observations, a thermotherapy regimesuitable to induce HSP70 alone or HSP70 and HSP90 may be determined forindividual tissues by those skilled in the art using well-knowntechniques for assaying gene expression. Individual tissues may notrespond identically as depicted in FIG. 3, but empirical observationsdemonstrate that the response of tissues to thermotherapy follows thepattern illustrated by curve 24.

A second round of therapy, timed 10 days to 14 days later (in order toallow time for autologous adaptive immunity to begin to develop) may befor longer duration (which would not necessarily require the use ofadditional or different implants) for a higher temperature level. Thesubsequent round of therapy can be designed to induce a panel of heatshock proteins that are induced by more severe heat shock (e.g.activating HSF1 and inducing HSP70, activating HSF2 and inducing HSP90and gp96). One example of this regime would be a setpoint temperaturerepresenting a ΔT=+4° C. for a duration of 90 minutes. Additional roundsof mild and moderate heat shock could be used to maximize tumor antigenpresentation to immunoresponsive cells, and lead to an immune responseto tumor cells, wherever they might reside in the body.

Advantages of initial moderate thermotherapy include minimization ofdamage to surrounding non-cancerous tissues, minimization ofdebilitating or damaging inflammatory responses, and maximizing theinduction of immune response. For additional background discussingantigenicity of heat shocked cells see:

-   -   (48) Ito, A., Shinkai, M., Honda, H., Wakabayashi, T., Yoshida,        J., and Kobayashi, T., “Augmentation of MHC Class I Antigen        Presentation via Heat Shock Protein Expression by Hyperthermia.”        Cancer Immunol. Immunother., 50: 515-522 (2001).    -   (49) Jolly, Caroline and Morimoto, Richard I., “Review: Role of        the Heat Shock Response and Molecular Chaperones in Oncogenesis        and Cell Death.” Journal of the National Cancer Institute, 92        (19): pp 1564-1572 (Oct. 4, 2000).    -   (50) Melcher, A. Todryk, S, Hardwick, N., Ford, M., Jacobson,        M., Vile, R. G., “Tumor Immunogenicity is Determined by the        Mechanism of Cell Death via Induction of Heat Shock Protein        Expression.” Nature Medicine, 4 (5): 581-587 (1998).

After heat shock has been used to induce antigen presentation (e.g. byHSP70), a more severe thermotherapy regime could be implemented toinduce apoptosis. Apoptotic cells may not allow presentation of antigensin the same manner as heat shocked cells, and therefore hold thepossibility of inducing a different immune response that could offerprotection against tumor cells that did not activate an immune responsevia mild heat shock. It is expected that thermotherapy sufficientlysevere to induce apoptosis would be in the range depicted at or abovethe curve 24 in FIG. 3, with degradation of apoptotic cells producingirreversible tissue effects. One predicted example of this regime wouldbe a setpoint temperature representing a ΔT=+8° C. for a duration of 90minutes. Relative thermotherapy regimes capable of inducing apoptosiswould need to be determined for different tissues using techniques wellknown to those skilled in the art of cell biology and moleculargenetics. In addition, induction of apoptosis by temperature stressoffers the possibility of tumor shrinkage arising from apoptosis oftumor cells. Induction of apoptosis in tumor cells offers the advantageof in situ shrinkage of tumor mass, at the same time as an immuneresponse against tumor antigens is induced. For additional backgrounddiscussing antigenicity of apoptotic cells see:

-   -   (51) Albert, M. L. et al., “Dendritic Cells Acquire Antigen from        Apoptotic Cells and Induce Class I Restricted CTLs.” Nature,        392: 86-89 (1998).

A subsequent round of thermotherapy can be used to induce necrosis ofcancerous tissues. Thermotherapy sufficiently severe to induce necrosiswould be in the range depicted above curve 24 in FIG. 3, producingirreversible tissue effects. One predicted example of a regime to inducetissue necrosis would be a setpoint temperature representing a ΔT=+15°C. for a duration of 90 minutes. Relative thermotherapy regimes capableof inducing necrosis would need to be determined for different tissuesusing techniques well known to those skilled in the art of cell biologyand molecular genetics.

Necrotic cells are more immunogenic than typical apoptotic cells (notethe inflammatory immune response activated by necrosis). See:

-   -   (52) Basu, Sreyashi, Binder, Robert J., Suto, Ryuichiro,        Anderson, Kirstin M. and Srivastava, Pramod K., “Necrotic but        not Apoptotic Cell Death Releases Heat Shock Proteins, Which        Deliver a Partial Maturation Signal to Dendritic Cells and        Activate the NF-κβ pathway.” International Immunology, 12 (11):        1539-1546 (2000).

FIGS. 36A-36G present a block diagrammatic representation a procedure ofthe invention. In particular, the procedure looks, not only to thecarrying out of the therapy with the purpose of achieving hyperthermiawith respect to targeted tissue but also looks to the use of generalthermal therapy procedures and associated controlled temperatures intime to evolve quanta of energy over time as above described optimizingthe overall treatment of neoplastic tissue and other treatment systemsincluding boney tissue repair, transplant support and viruses.Additionally, as discussed with the structuring of the implants earlierherein, adjunct therapies as chemotherapy can be provided with thesystem in a manner wherein release agents are dispersed non-invasively.This is carried out by temperature controlled application of radiativeheat generating energy at prescribed agent application intervals. Ingeneral, for the former adjunct therapeutic approach, the thermotherapyis utilized to initially create reversible tissue effects by theapplication of energy in time quanta falling below the critical curve 24described in conjunction with FIG. 3. Thereafter, quanta election may beselected to cause the tissue to be subjected to treatment above thatcritical curve to evoke denaturization or irreversible tissue effects.As noted earlier, the thermotherapy approach at hand also can becombined with radiation therapy or with a triple modality approach. (Seepublication 10).

Looking to FIG. 36A, the procedure is seen to commence at node 500 andline 502 leading to the determinations set forth at block 504. Thosedeterminations provide for the election of target therapy temperature(s), for instance, for hyperthermia with HSP induction andsusceptibility to adjunct therapies such as radiation therapy,chemotherapy. i.e., release agent disbursement by heat activation, bonytissue mending and the like. The procedure then continues as representedat line 506 and block 508 providing for the user selection of implantsensor (s) thermal responses based upon the elected target therapysetpoint temperature or temperatures. Particularly during hyperthermiatreatments, the measurement of the actual temperature distribution inthe tumor or immediately adjacent tissue is highly important. Seepublication (10) supra. With temperature elections having been made andsensor component/heater component configurations determined, then asrepresented at line 510 and block 512 the power level for the ACFheating assembly 94 is selected and set by the user. Where therapy suchas the induction of heat shock proteins has been elected as the basicprocedure, then as represented at line 513 and block 514 the user mayevolve a maximum therapy duration at elected target temperature ortemperatures to establish energy quanta of thermal application to thetarget tissue volume. The election of such maximum value(s) is made withrespect to hyperthermia treatment to avoid generation of temperatures ortemperature in time conditions falling above the critical curves as at24 described in connection with FIG. 3. The procedure then continues asrepresented at line 515 and block 516 providing for the administrationof general or local anesthetic agent as required. Then, as representedat line 518 and block 520, using one or more of the above-discussedimaging techniques, or as part of an intra operative procedure, theimplant is inserted into or adjacent to the target tissue volume of thepatient utilizing an implant device, for example, as discussed inconnection with FIGS. 32 and 33. In connection with this implantation,where more than one implant sensor component is to be employed withinthe target tissue, then a positional magnetic flux response may beachieved by providing an orientation of the implant with respect to thedirection of magnetic flux lines. In this regard, the orientation withrespect to magnetic flux lines will effect the level of amplitude of theresponse of the magnetometer assembly 104. Such responses can becorrelated to specific sensor component locations. Additionally, as partof this procedure, the exterior of the patient's body is marked toindicate the closest location of the implant or implants so as tofacilitate the positioning of the radiative heating coil or antenna aswell as to orient the pick-up structure of the magnetometer.

Next, the methodology provides a confirmational procedure as representedat line 522 and block 524 wherein the imaging and other suchinstrumentation are used for purposes of ascertaining if the implantsare in the proper location with respect to the target tissue. Should theimplant positioning not be appropriate, then as represented at loop line526, the method reverts to the procedure described in connection withblock 520. Upon an affirmative determination with respect to the queryposed at block 524, then as represented at line 528 and block 530 thepatient is positioned on the treatment support such as a table or chairso that the earlier located marker or outline on the surface of thepatient is visible for the next step in the procedure. That stepprovides for locating the ACF heating coil or microwave antenna as wellas the magnetometer probe at the proper locations with respect to theskin of the patient.

The procedure then continues as represented at line 532 and block 534wherein, guided by the marker at the skin surface of the patient, theheating coil 98 or microwave antenna is positioned as close as practicalwith respect to the skin of the patient to sensor/heater implants. Themethod then continues as represented at line 536 which reappears in FIG.36C extending to block 538 providing for turning on control 112 (switch180 illuminating green LED 182). Then, as represented by line 540 andblock 542, the operator selects the duty cycles. Reverting momentarilyto FIG. 7, it may be recalled that the operator selects the interval,δt₁ during which interval the ACF heating assembly 94 is activatedfollowing which that assembly is deactivated to eliminate the potentialfor electrical noise phenomena and the like and an interval ofinterrogation or monitoring of the sensor implants, δt₂ follows. Thatmonitoring is carried out in conjunction with magnetic field intensitieswhich are relatively low. As described in connection with FIG. 5, theduty cycle election is undertaken with switch function 184. Table 1 setsforth ranges for these selections. ^(δ)t, may range from about 0.01 toabout 30 seconds and preferably from about 0.05 to about 5 seconds. δt₂may range from about 0.005 to about 5 seconds and preferably from about0.02 to about 1 second. Next, as represented by line 544 and block 546the operator proceeds to select the extent of travel of the table orplatform 52 or corresponding chair support. That selection is made atconsole 112, the operator actuating up/down switches 194 while observingthe corresponding locus of travel shown at display 196. The program thencontinues as represented at line 548 which extends to block 550providing for the acquisition of the enabling voltage value of the motorcontrol 78. Following such acquisition, as represented at line 552 andblock 554 a determination is made as to whether that enabling voltageV_(mc) is greater than or equal to, for example, three volts. If thedetermination at block 554 is that the enabling voltage of the tablecontrol is not adequate, then as represented at line 556 and block 558,an error message is displayed at the display 204 (FIGS. 5 and 8A). Theerror, in general will indicate that the control leads 84 from theoscillation system are not properly attached to the console 112. Theprogram then continues as represented at line 560 and block 562 whereinthe display 204 outputs a display prompt, to wit: “check the lead/cableattachment”. The program then reverts to line 548 as represented at line564.

In the event of an affirmative determination with respect to the queryposed at block 554, then as represented at line 566 and block 568 greenLED 210 is illuminated (FIGS. 5 and 8B) and the procedure proceeds asrepresented at line 570 and block 572. In this regard, the operatorcarries out what in effect is a “check run” of the oscillation ofplatform 52 or chair or equivalent patient support. This check isinitiated by actuating button switch 198 (FIGS. 5 and 8B). As thepatient support assemblage 54 is activated, the procedure then evaluatesthe status of the magnetometer 104. Accordingly, as represented at line574 and block 576 (FIG. 36D) the magnetometer 104 is turned on and thesystem acquires its on and continuity status information. The programthen continues as represented at line 578 and block 580 wherein adetermination is made as to whether the status of the magnetometer 104is ok. In this regard, the peak-to-peak variation of the magnetometeroutput voltage, V_(MO) is compared with a reference, V_(FM). Where thatcondition obtains, then the enablement signal, V_(C) is generated. Thissignal must be greater than or equal to, for example, three volts d.c.to be representative. In the event that the magnetometer status is notok, then as represented at line 582 and block 584, an error condition isdisplayed at display 204 indicating that the magnetometer probe cable108 or the cable 114 to console 112 is not properly attached. Theprogram then continues as represented at line 586 and block 588 todisplay the prompt to the operator to check the magnetometer cableattachments. The program then returns as represented at line 590 to line578.

Where the query posed at block 580 is responded to in the affirmative,then as represented at line 592 and block 594 green LED 212 at console112 is illuminated and the program continues as represented at line 596and block 598. At this juncture in the procedure, the operator will bepositioning the magnetometer probe 106 as close as practical to theimplants. This positioning will involve orientation of that probe toachieve a maximum magnetometer signal change with the oscillations ofthe platform 52. The program then continues as represented at line 600.

As an optional procedure, the instant system may utilize, theorientation of sensor components having a principal elongate dimensionor, as noted above, an aspect ratio of less than unity such that whensubjected to magnetic flux lines, for example, of the earth's magneticfield, the disturbance that evokes, if any, depending upon the state ofpermeability, will draw a response at magnetometer assembly 104, theamplitude of which will vary depending upon that orientation. Thus, byinitially selectively orienting the sensor components, the magnetometerfunction may discern their location in a lateral, as it were, scanningaspect resulting from the oscillation of platform 52. In this regard,that aspect of interrogation is one generally normal to the longitudinalorientation of the probe component 106. Of course, probe orientationwill be dependent upon the particular mechanism employed for thatfunction. However, where sensor amplitude-based positional informationis desired, then as represented by optional dashed line 602 and dashedblock 604 the system will acquire sensor-based magnetic responseamplitude values with respect to each implanted sensor. The program thenreverts, as represented at dashed line 606 to line 600. Line 600 extendsto block 607 (FIG. 36E) providing for the termination of the test run ofthe support assemblage 54. This is carried out by operator actuation ofthe stop button switch 202 on console 112 (FIGS. 5 and 8B).

The procedure continues as represented at line 608 and block 609 whichprovides for the operator switch-based selection of both therapyduration commencing with the attainment of setpoint temperature, T_(SP)and the maximum allotted time to attain T_(SP). Insertion of thistemporal data is made with switches 190 and 191 in conjunction with thevisual readout at numerical display 192.

The ACF heating assembly actuation next is addressed as represented atline 610 and block 612 providing that the ACF heating assembly 94 isturned on and, as represented at line 614 and block 616 a query is posedas to whether the ACF heating unit is enabled both by the development ofa requisite on voltage level, V_(RF) as being greater than or equal tothree volts and the presence of the earlier-described magnetometersignal V_(C) as being greater than or equal to three volts. If thoseANDed conditions are not met, then as represented at line 616 and block618 an error visual cue is displayed at display 204 indicating that thecontrol leads 102 are not properly connected to the control console 112.The program then continues as represented at line 620 and block 622 todisplay a prompt advising the operator to turn off the ACF heating unitand check the cable attachment 102 extending to the console 112. Theprogram then reverts to line 610 as represented at line 624.

Where the query posed at block 616 results in an affirmativedetermination, then as represented at line 626 and block 628 green LED211 at console 112 is illuminated and the program continues asrepresented at line 630. Line 630 extends to the query posed at block632 determining whether the duration for therapy and the maximum timeallocated for reaching T_(SP) have set to correct and intendedintervals. These times are set by the operator employing the up/downswitches 190 and election switch 191 in conjunction with display 192 onconsole 112. It may be recalled that for adjunct therapies to HSPinduction such as the temperature controlled dispersion ofchemotherapeutic release agents, proteins and/or combined radiationtherapy, one or more levels of predetermined Curie transitiontemperatures may be utilized in conjunction with a correspondingsequence of sensor component containing implants. In the latter aspect,such therapy may involve maintenance of the quantum of thermal energybelow critical curves as at 24 described in connection with FIG. 3.Where a time interval is incorrect, then as represented at line 634 andblock 636 appropriate adjustment of control switches 190 and 191 is madeand the program reverts to line 630 as represented at line 638. Ingeneral, therapy duration is timed commencing with the attainment ofsetpoint temperature, T_(SP) for HSP-based procedures.

Where the query posed at block 632 is responded to in the affirmative,then as represented at line 640 and block 642 a determination is made asto whether the therapy time elapsed indicates zero minutes. This readoutis provided at console 112 at display 222. In the event that thatdisplay does not register zero minutes, then as represented at line 644and block 646 reset button switch 224 is actuated and the programcontinues as represented at lines 648 and 640. With the therapy timeelapsed set at zero, the procedure continues as represented at line 650and block 652 FIG. 36F). Block 652 reflects the activity of controller240 (FIG. 8B) in carrying out a determination that the conditionsestablished by the illumination of LEDs 210-212 at console 112 have beensatisfied and the system is now ready to commence a thermal therapymode. In the event that the ready check fails, then as represented atline 654 and block 656 an error cue is published at display 204 and, asrepresented at line 658 and node A the program reverts to line 548 toagain consider the ready checks.

In the event the query posed at block 652 results in an affirmativedetermination, then as represented at line 660 and block 661 thermaltherapy which may comprise hyperthermia therapy commences with theoperator actuation of the start therapy button switch 220 at console112. With this actuation, as represented at line 662 and block 664, thegreen LED 213 indicating that therapy is in progress at console 112 isilluminated and the procedure continues as represented at line 666 tothe query at block 668. Therapy being underway, but setpoint temperatureT_(SP) not having been reached, the program determines whether or notthe stop therapy button switch 226 at console 112 has been actuated. Inthe event that such an actuation occurred, then as represented at line669 and block 670 the ACF heating assembly 94 is turned off as well asthe motor control circuit 78 of the support assemblage 54. As a visualcue that the therapy is stopped, red LED 228 is illuminated and,correspondingly, green LEDs 200 and 213 are de-energized. The procedurethen continues as represented at line 671 and block 672 wherein theoperator determines whether or not the therapy mode is to be resumed. Inthe event that it is to be so resumed, then as represented at line 673and block 679, to resume the therapy mode for the duration of theunlapsed therapy, the start therapy button switch 220 is actuated atcontrol console 112 which, in turn, causes the turning off of red LED228 and the turning on of green LEDs 200 and 213. This automaticallyrestarts the platform 52 oscillation and the activation of the ACFheating assembly 94. As noted above, for HSP induction procedures,therapy duration is timed from the attainment of setpoint temperature,T_(SP). If that setpoint value has not been reached in the presence of astop command, the system, upon re-start, will proceed to derive T_(SP)and then commence therapy duration time-out. The program then continuesas represented at line 675 which extends to line 666.

Where the query posed at block 672 results in a determination thattherapy is not to be resumed, then as represented at line 676 and node677 the therapy is ended.

Returning to block 668, where a determination has been made that thestop therapy switch 226 has not been actuated, then as represented atline 678 and block 679 (FIG. 36G) a determination is made as to whetherthe target or set point temperature, T_(SP), has been reached. Thistarget temperature has been discussed in conjunction with dashed line142 in connection with FIG. 7. See also the ranges for T_(heater) inTable 1. Where the target or set point temperature has been reached,then as represented at line 680 and block 682 a determination is made asto whether the maximum allotted time for the system to reach thesetpoint temperature, T_(SP) has occurred before the target temperature,T_(SP) has been reached. If that time limitation for acquiring setpointtemperature has not been reached at this juncture, then as representedat line 684 and block 688, the therapy duration timeout is commencedwith the acquisition of setpoint temperature T_(SP). As discussed abovein connection with block 668 if the stop therapy button has been pressedand therapy has been resumed as discussed in connection with block 674,then a commencement of a continuation of the therapy duration intervalis made. The program then continues as represented at line 690 and block692 providing for the illumination of green LED 215 on console 112. Theprogram then continues as represented at line 694. Where the targettemperature has not been reached, then as represented at lines 696 and694, the program continues to the query posed at block 698. Block 698determines whether or not the therapy time elapsed as displayed atdisplay 222 on console 112 has reached a therapy duration valuation. Inthe event that it has not, then as represented at line 700 and block702, the time elapsed display 222 is updated and, as represented at line704 the program reverts to line 666.

Returning to block 682, where the maximum time for reaching setpointtemperature, T_(SP) has been reached before the attainment of setpointtemperature, then an error is at hand and is represented at line 708 andblock 710, an error signal is visually displayed which may beaccompanied by an acoustical cue. The program then continues asrepresented at line 712 to line 706.

Line 706 extends to block 720 which provides for the deactivation of theactive components of the system. In this regard, the ACF heatingassembly 94 is deactivated as is the magnetometer assembly 104. Controlcircuit 78 for the platform support assemblage 54 is deactivated.Therapy complete green LED 214 is illuminated and green LED 213representing therapy in progress is de-energized. The program thencontinues as represented at line 722 and block 724 wherein pertinentdata for the procedure parameters is recorded. It may be recalled thatthis data can be displayed at display 204 by the actuation of buttonswitch 206. The procedure then continues as illustrated at line 724extending to node 726 representing a therapy ended stage.

Hyperthermia currently is employed for purpose of limiting restenosis atthe location of implanted stents in blood vessels. In general, suchstents, for example, may be utilized in percutaneous transluminalcoronary angioplasty (PTCA) for purposes of avoiding a collapse ofarteries subsequent to balloon implemented dilation. As in otherthermotherapeutic procedures, necessary sensing of temperatureheretofore has been carried out in an invasive manner. This priorapproach is illustrated in connection with FIGS. 37 and 38. In thefigures, a stent is shown generally at 740 as it is implanted within ablood vessel, the walls of which are shown at 742. Having a typicalmesh-like structuring and cylindrical shape, the stent 742 is configuredwith an outwardly disposed cylindrical contact surface positioned incontact with the intima region of blood vessel 744. To applythermotherapy, for example, by ACF heating from an external applicator,while assuring that accurate temperature control over the stent 740 ismaintained, it is necessary to locate a transluminal catheter bornethermal sensor 746 within the stent structure 740. Sensor 746 may beprovided, for example, as a thermister mounted at the tip of a catheter747. As is apparent, this invasive positioning of the temperature sensor746 is required each time the hyperthermia therapy is performed, aprocedure which may be called for relatively often. In addition to therisk of this invasive positioning of the temperature sensor 746, thecatherization of the patient involves a substantial cost. See thefollowing publication in this regard:

-   -   (53) Stefanidas, C. et al., “Hyperthermia of Arterial Stent        Segments by Magnetic Force: A New Method to Eliminate Intimal        Hyperplasia.” Journal of the American College of Cardiology,        37 (2) Supp. A: 2A-3A (2001).        -   See additionally European Patent Application No. EP            1036574A1.

FIGS. 39 and 40 illustrate an initial embodiment for a stent formed ofnon-magnetic material which can be heated from an externally appliedenergy source, for example by alternating current field heating andwhich initially incorporates an untethered temperature sensor which isfixed to it prior to implantation. Looking to FIGS. 39 and 40, themesh-structured stent is represented generally at 748 extending about acentral axis 749. Stent 748 will be formed of a non-magnetic inductivelyexercisable material, for example, austenitic stainless steel such asType 316, titanium, titanium alloys and nitinol. Typically, stents areformed of a non-magnetic material inasmuch as they often will be locatedwithin the imaging field of highly magnetic devices such as MRI systemsand the like. Typical stent structures are described in the followingpublications:

-   -   (54) Interventional Vascular Product Guide, Martin Dunitz, Ltd.,        London (1999).    -   (55) Handbook of Coronary Stents, 3rd ed., Martin Dunitz, Ltd.,        London (2000).

The mesh-like generally cylindrically-shaped stent 748 is seen to beimplanted such that its outwardly disposed contact surface will havebeen urged into abutting and fixed intimate connection with the intimaof blood vessel 752. Fixed in intimate thermal exchange relationship tothis contact surface 750 at the central region of the stent 748 is anuntethered temperature responsive component assembly representedgenerally at 754, the outwardly disposed surface of which at 756 is seento slightly additionally distend blood vessel 752 at region 758. Sensorcomponent assembly 754 is seen to be formed of four discrete components754 a-754 d which, as in the earlier embodiments may be fashioned of asoft ferromagnetic material, i.e., a soft ferrite having a Curie pointtemperature elected to provide a significant change in magneticpermeability, for example, a 20 to 1000 fold change over a relativelynarrow range of temperature change, for example, between about 0.1° C.and about 1° C. The sensors 754 a-754 d are intimately bonded with thenon-magnetic metallic stent 748 and their securement may be furtherassured by the positioning of a biocompatible flexible sheath or band760 over the central portion of the stent 748 and over the outwardlydisposed surfaces of the sensor component assembly 754. Band 760 may,for instance, be formed of a silicone elastomer, Dacron, Teflon,titanium, nitinol or a Type 316 stainless steel. Multiple temperaturesensing components 754 a-754 d are used for the component assembly 754in the interest of providing operational redundancy and for the purposeof providing a structural aspect wherein the sensor assembly 754exhibits a flexibility called for to accommodate tortuous access throughthe vasculature of the body and placement, for example, of the stent 748within a curved blood vessel as opposed to a vessel exhibiting morestraight or uncurving characteristics. An intimate thermal exchangerelationship is called for between the stent 748 and the untetheredtemperature responsive component 754. In this regard, the preferredthermal resistance, TR₄ between the stent 748 and the sensors 754 a-754d will be about 0.5° C./watt, while the nominal thermal resistance, TR₃will be about 5° C./watt. Providing a biocompatible electricallyinsulative conformal coating such as the earlier-described “Parylene” asshown at 762 in FIG. 40 is beneficial and promotes the adhesion of thecomponents 754 a-754 d to the outer tissue contact surface 750 of stent748. In general, stents as at 748 will have a length, L₅ of betweenabout 0.12 inch (3 mm) and about 3 inches (76 mm) and preferably willfall within a length having a range of about 0.2 inch (5.1 mm) and about2 inches (51 mm). For such stents, the sensor assembly 754 will have alength, L₄ of between about 0.06 inch (1.5 mm) and about 1.5 inch (38mm) and preferably between about 0.1 inch (2.5 mm) and 1 inch (25.4 mm).The length, L₆ of each of the components 754 a-754 d will be betweenabout 0.03 inch (0.76 mm) and about 0.75 inch (19 mm) and preferablywill fall within a range of about 0.05 inch (1.3 mm) and about 0.5 inch(12.7 mm). The widthwise or circumferential extent, W₆ of the sensorcomponents 754 a-754 d will fall in a range of about 0.01 inch (0.25 mm)and about 0.50 inch (12.7 mm) and preferably will fall within a range ofabout 0.03 inch (0.75 mm) and about 0.20 inch (5.1 mm). The thickness,t₅ of the components 754 a-754 d, as diametrically established ingeneral will fall within a range of from about 0.01 inch (0.25 mm) toabout 0.50 inch (12.7 mm) and preferably within a range of from about0.03 inch (0.75 mm) to about 0.20 inch (5.1 mm). Spacing, W₇ for the gapextending between the stent sensor components 754 a-754 d will fallwithin the range of from about 0.005 inch (0.13 mm) to about 0.1 inch(2.5 mm) and preferably within a range of from about 0.01 inch (0.25 mm)to about 0.05 inch (1.3 mm). Flexible support band 760 will have athickness, t₆ which will fall within a range of from about 0.0001 inch(0.0025 mm) to about 0.05 inch (1.3 mm) and preferably will fall withina range of from about 0.001 inch (0.025 mm) to about 0.03 inch (0.76mm). Biocompatible coating 762 will have the earlier-described range ofthicknesses, t₂.

The technique and instrumentation discussed in connection with FIGS. 5through 8A and 8B essentially are repeated for the therapy assigned tolimit restenosis utilizing stents as at 748. In this regard, looking toFIG. 41, the instrumentation and support equipment discussed inconnection with FIG. 5 are illustrated in connection with a patient 770.Patient support components, heating components and sensing componentswhich are repeated are shown with the same earlier presented numericalidentification but in primed fashion. Note in the figure that stent 748reappears adjacent the heart region 772 of patient 770. Heatingcomponent 98′ extending from the ACF heating assemblage 94′ is locatedin adjacency with the stent 748 and the pick-up 106′ of magnetometerassembly 104′ is positioned in external adjacency with the location ofstent 748. Power is applied from the heating unit or assembly 94′ on anintermittent basis as earlier-described in conjunction with FIG. 7 topermit a power input interval earlier-described at δt₁ followed by ameasurement or interrogation interval earlier-described at δt₂. Timeranges for this intermitting remain as earlier identified at δt₁ and δt₂in Table 1. The setpoint, T_(SP) is established for restenosis therapyby design of the sensor component assembly 754 and the associated narrowCurie transition temperature. ΔT_(S) as described at 156 in FIG. 7 nowtermed δT_(stent) or temperature range of the stent about the setpointfalls in a temperature range of nominally from about 0.1° C. to about 5°C. and preferably will fall within a range of about 0.1° C. and 3° C.The instantaneous heating power generated within the stent 748, Pstent,will generally fall within a range of from about 0.05 calories/second toabout 20 calories/second and preferably will be within a range ofbetween about 0.1 calories/second and about 10 calories/second. Asdescribed in conjunction with FIG. 7, as Curie transition temperature isreached the permeability of the sensor component assembly 754 decreasessomewhat dramatically, i.e., a 20 to 1000 fold change, whereupon poweris terminated until temperature diminishes to evoke the heating patternsas have been discussed at 156, 166 and 172 in connection with FIG. 7.The nominal hyperthermia therapy temperature for stents such as at 748(T_(stent)) will fall within a range of from about 39° C. to about 70°C. and preferably within a range from about 41° C. to about 50° C.

The combined stent and unthethered sensor component assemblies discussedin conjunction with FIGS. 39 and 40 also may be utilized to implement athermally activatable drug release feature. Referring to FIGS. 42 and43, a stent represented generally at 778 is shown having been implantedwithin a blood vessel 780. Attached in intimate thermal exchangerelationship with the outer contact surface 782 of stent 778 extendingabout a central axis 779 is a sensor component assembly representedgenerally at 784 which, as before, is formed of four untetheredtemperature responsive components 784 a-784 d which, along with thestent 778 are configured and spaced with the same dimensional andoperational parameter ranges described in conjunction with FIGS. 39 and40 and summarized in Table 1. Each of the temperature responsivecomponents 784 a-784 d is fixed in thermal exchange relationship withthe contact surface 782 present as the outwardly disposed surface ofstent 778. The temperature responsive component assembly 784 is coatedas before, by an electrically insulative conformal biocompatible coating786 such as the earlier-described “Parylene” which further functions toaid in the securement of the four segments 784 a-784 d to surface 782.This securement further is enhanced by the flexible band or sheath 788surmounting both the stent 778 and the sensor assembly 784. Band 788 isstructured in the manner of earlier-described band 756. Note, howeverwith the arrangement of FIGS. 42 and 43, that the inward surface 790 ofstent 778 is coated with a thermally activatable drug release coating asshown at 792. The surface coating 792 is revealed in FIG. 43 as having athickness, t₈ which may fall within a range of about 0.001 inch (0.025mm) to about 0.20 inch (5.0 mm) and preferably will fall within a rangeof from about 0.005 inch (0.13 mm) to about 0.10 inch (2.5 mm). Suchdrugs may be provided, for example, as paclitaxel and the antibioticSirolimus as well as antithrombogenic agents such as heparin and thelike. See the following publications in this regard:

-   -   (56) Simonsen, “Percutaneous intervention arena still expanding        for heart disease.” Cardiovascular Device Update, 7 (4): 2-5        (May 2001).    -   (57) “Drug-Coated Stents Poised for Growth”, Cardiovascular        Device Update,; 7 (9): 8-9 (September, 2001).

The nominal drug release temperature, T_(DRS) will range from about 39°C. to about 65° C. and preferably from about 41° C. to about 50° C. Drugrelease coating 792 when non-invasively heated to a drug releasingtemperature provides a controlled amount of a selected drug at the situsof the stent 778 to limit restenosis phenomena. Such a drug releaseprocess can be repeated at therapeutic intervals which may range fromweeks to months to even years. Additionally, the coating may beactivated in the event the patient's symptoms or diagnostic methodsindicate that restenosis is occurring and progressing to the point thattherapeutic intervention is warranted. Where hyperthermal therapy iscombined with drug release activity, sensor segments or components 784a-784 d may be assigned corresponding different setpoint or targettemperatures (Curie transition temperatures).

The untethered temperature responsive component assembliespreferentially are positioned on the outer contact surface on the stentstructure as described inasmuch as such location provides a factor ofsafety with respect to the adhesion of the individual components to thatcontact surface. Should the coupling be damaged, the sensor componentsare retained by the stent structure itself outside of luminal bloodflow.

This outboard positioning of the untethered temperature responsivecomponent assemblies can be arranged with additional redundancy bymounting them, for instance, at diametrically opposite locations uponthe stent contact or outer surface. FIGS. 44 and 45 present such anarrangement wherein the nonmagnetic material stent as representedgenerally at 800 is shown implanted within a blood vessel 802. Asbefore, the stent 800 is formed about a central axis 803 with agenerally mesh-like structuring having an outwardly disposed contactsurface 804 of generally cylindrical configuration to which untetheredtemperature responsive component assemblies represented generally at 806and 808 are mounted in intimate thermal exchange relationship. Assembly806 is seen to be formed of discrete untethered temperature responsivecomponents 806 a-806 d while, correspondingly, assembly 808 is formed ofdiscrete untethered temperature responsive components 808 a-808 d. Eachof these components is coated with an electrically insulative, conformalbiocompatible material shown respectively at 810 and 812 in FIG. 44.That material, which may be the earlier-described “Parylene” furtherfunctions to enhance the bond between the assemblies 806 and 808 and theouter surface 804. Assemblies 806 and 808 further are secured to theouter surface 804 by a flexible band or sheath 814. Band 814 isstructured in the manner of earlier-described band 756. As before, thefigures reveal that the blood vessel 802 is diametrically enlarged atregions 816 and 818 to accommodate for the thicknesses of the assemblies806 and 808. These assemblies and the stent structure 800 as well ascoatings and the like will have the same dimensions and operationalparameters as discussed above and summarized in Table 1.

As noted earlier, essentially all metallic stents which have beenimplanted are formed of nonmagnetic material in view of the potentialinvolvement of highly magnetic imagining systems, e.g., MRI devices. Asa consequence, those pre-implanted stents can be retrofitted in vivowith the temperature sensing aspects of the present invention to permitnoninvasive therapeutic procedures for subsequent treatment ofrestenosis phenomena. The retrofitting approach, in effect, provides forthe installation of a temperature responsive component containingstent-like structure diametrically expandable within the preexistingstent.

Referring to FIGS. 46 and 47, an asymmetrical retrofitting design isillustrated. In the figure, a conventional nonmagnetic metal mesh stentis represented in general at 824 which has been previously implantedwithin a blood vessel 826. In this regard, note that the outwardlydisposed surface 828 of the stent 824 is in contact with the intima ofthe vessel 826. The untethered temperature responsive component assemblycarrying insert or support member is seen at 830 with a central axis 831and having a generally cylindrical support member defining interiorlydisposed surface 832 and an exterior surface 834 to which the untetheredtemperature responsive component assembly represented generally at 836is bonded in thermal exchange relationship. Note, in this regard, thatthe assembly 836 is formed of four discrete temperature responsivecomponents 836 a-836 d. In general the stent insert device may be formedwith essentially the same mesh structuring and material as present inthe previously implanted stent 824. Such mesh structuring is not shownin the figures in the interest of illustrational clarity. FIG. 47 showsthat each of the components 836 a-836 d is coated with a biocompatiblecoating such as the earlier-described “Parylene” material. Additionally,the structural integrity of their attachment with the support member 830is enhanced by a flexible band 840. Sensor carrying support member 830is inserted within the preexisting stent 824 using balloon angioplastyprocedures. In order to accommodate for the asymmetrical positioning ofonly a single sensor assembly 836, the member 830 is structured so thatit is preferentially expandable in the region 842 (FIG. 47) immediatelybeneath the temperature responsive component assembly 836. Accordingly,upon balloon expansion during the placement of member 830, and itssupported sensors, the region 842 will expand from an initial insertiondiameter diametrically outwardly against the interior surface 844 of thepreexisting stent 824 to create the crimping expansion of the contactingsurface of that stent 824 as represented at region 846. Preferentialexpansion at sub-stent 830 region 842 can be provided by structuring thestent to be thinner at that region and/or the mesh structure openingsize may be asymmetrically varied. Conventional characteristics againare identified in FIGS. 46 and 47 as L₄, L₅, L₆, W₆, W₇, t₅ and t₆. Thedimensional ranges associated with these symbols remain as describedabove and as tabulated in Table 1. Similarly, the temperature range ofthe stent 824 around setpoint temperature, ΔT_(stent) remains asdescribed above and tabulated. The instantaneous heating power generatedwithin the stent, P_(stent) remains as described above and set forth inTable 1 and the thermal resistance values between the stent and sensorassembly remain as described in connection with the identifiers TR₃ andTR₄ set forth above and in Table 1. Devices as at 830, in addition tobeing formed of biocompatible material, are formed of a materialselected to avoid any Galvanic activity with the pre-existing stent,i.e., an agalvanic material.

Referring to FIGS. 48 and 49, a retrofitting or “stent within a stent”approach is illustrated wherein the untethered temperature responsivecomponent assembly is symmetrically diametrically duplicated. In thefigures, a pre-implanted nonmagnetic stent is represented generally at850. As before, stent 850 has a mesh-type structure of generallycylindrical configuration, the cylindrical outer surface 852 of which isin abutting compressive engagement with the intima of blood vessel 854.In order to carry out a hyperthermia form of treatment for restenosiswith the necessary highly accurate temperature control, a secondarystent or support member represented generally at 858 extending about acentral axis 859 is implanted within the interior surface 856 of stent850. Secondary stent 858 is formed of an expandable mesh material andfunctions to support diametrically oppositely disposed temperaturesensor component assemblies represented generally at 860 and 862. Topromote the flexibility of the support member stent 858, the temperaturesensor component assemblies 860 and 862 are each formed of four ferritesensing elements again exhibiting accurate and narrow Curie temperaturetransition phenomena. Assembly 860 is seen to be formed of ferritesensors 860 a-860 d. As before, by utilizing such a sequence of thesensors, a modicum of flexibility is provided to aid in maneuvering thesecondary stent 858 into position for connection with the primary stent850. Assembly 862 is similarly fashioned with four sensor componentsexhibiting the same sharp Curie temperature transition phenomena andbeing shown at 862 a-862 d. Similar to the embodiment of FIGS. 46 and47, the secondary stent 858 is configured with an internal wall formedof mesh material compatible with the material forming the primary stent850. Such mesh structuring is not shown in FIG. 48 in the interest ofillustrational clarity. The interior wall of device 898 wall is shownhaving an interior surface at 864 and an exterior surface 866 upon whichthe sensor component assemblies 860 and 862 are connected. To enhancethis connection, a flexible band surmounts both the cylindrical exteriorwall 866 and the assemblies 860 and 862. FIG. 49 reveals that each ofthe components of the assemblies 860 and 862 are coated with anelectrically insulative biocompatible conformal coating such as theearlier-described “Parylene”. The coatings are revealed in FIG. 49 at870 c in conjunction with sensor component 860 c and at 872 c inconjunction with sensor component 862 c. As before, the conformalcoatings will have a thickness range identified earlier herein as, t₂and further set forth in Table 1. Sensor segments 860 a-860 d and 862a-862 d are spaced apart a gap identified as W₇; each has an individualdiscrete length identified as L₆ and the assemblies 860 and 862 havelengths identified as L₄. Each of the components 860 a-860 d and 862a-862 d have thicknesses identified as t₅ and widthwise dimensions asshown in FIG. 49 identified as W₆. All of these dimensions are tabulatedin Table 1 and have been discussed above. Placement of the secondarystent 858 may be by balloon pressure to an extent creating thesymmetrically disposed outward deformations in the wall of stent 850 asshown at 874 and 876. Those deformations generally will have the lengthL₄ while the overall length of the principal stent 850 will have lengthranges identified as L₅ in Table 1 and as described above.

By virtue of the intimate association of the secondary stent bornetemperature sensor component assemblies 860 and 862 with the stent 850,ΔT_(stent), the temperature range of the stent 850 about thehyperthermia therapy set point may be maintained within theearlier-described range from about 0.1° C. to about 5° C. and preferablyfrom about 0.1° C. to about 3° C. The intimate association also permitsdevelopment of the nominal hyperthermia therapy temperature for thestent 850, T_(stent) within the earlier-noted range of from about 39° C.to 70° C. preferably between about 43° C. and 48° C. A nominal stentheating temperature of 45° C. has been described in publication (53)supra.

See additionally the following publication:

-   -   (58) Thury, A., et al., “Initial Experience With Intravascular        Sonotherapy For Prevention Of In-Stent Restenosis; Safety And        Feasibility”, J. of Am. College of Cardiology 37 (2)        Supplement A. (2001)

In general the setpoint temperature, T_(SP), is elected as beingeffective for inhibiting the proliferation of intimal hyperplasia growthfollowing stent insult. The nominal thermal resistance between theretrofitted stent 850 and the sensor assemblies 860 and 862, TR₃continues to be 5° C./watt and the preferred thermal resistance, TR₄remains 0.5° C./watt. Because of the symmetry of positioning of thetemperature sensor assemblies 860 and 862, a balloon evoked placementcan be carried out without customized structuring of the secondary stentcylindrical wall as provided in conjunction with the embodiment shown inFIGS. 46 and 47.

The discourse now turns to the procedures associated with theembodiments described above in connection with FIGS. 41-49.

Looking to FIG. 50A, the initial phase of the procedure involves thepositioning of a stent transluminally within the patient. That stenttypically will be positioned as part of percutaneous transluminalcoronary angioplasty (PTCA). For the instant method, the stent willincorporate an integral temperature sensing system and may furtherincorporate heat activatable drug components. Accordingly, the generalprocedure will involve the administration of a general or localanesthetic agent as indicated at block 890. Then, as represented at line892 and block 894 the stent with integral sensor is positioned withinthe patient's blood vessel at the targeted location and, typicallyutilizing balloon procedures, the stent is deployed such that it issecurely imbedded. Then the delivery catheter is removed from thepatient and, as represented at line 896 and node 898 the stentpositioning phase will have ended. It is subsequent to this phase, atime interval that may range from weeks to years that restenosisconditions may arise.

As an alternate to the procedure thus far described, the secondary stentapproach described in conjunction with FIGS. 46-49 may be carried out asrepresented at block 900. With this procedure, a stent which has alreadybeen implanted is supplemented with temperature sensor componentsaccording to the invention by catheter placement and expansion within apreexisting stent.

Subsequent to the stent positioning phase the patient will be monitoredfor the occurrence of clinically significant restenosis. As representedat block 902 such checks may be carried out, for instance, usingangiography, diagnostic ultrasound, x-ray, or MRI techniques. Theprocedure then continues as represented at line 904 and block 906presenting a query as to whether or not evidence of restenosis ispresent. In the event that it is not, then as represented at line 908,block 910 and line 912 such checks are continued, the patient'scardiac/circulatory function being monitored on a periodical basis.Where evidence of restenosis does exist, then as represented at line 914and block 916 thermal therapy according to the invention is commenced.As an initial step in the procedure, a marker is placed on the skin ofthe patient at a location selected for aiding in the positioning of themagnetometer probe 106′ and the ACF heater coil 98′. As represented atline 918 and block 920 the patient is positioned on the table as at 52′or suitable chair so that the skin locative marker is clearly visiblefor the noted coil and probe orientation. Then, as represented at line922 and block 924 the ACF heating coil positioning mode is commenced. Inthis regard, using the marker at the surface of the patient the heatingcoil 98′ is located as close as practical to the location of thestent/sensor implant or implants. Then, as indicated by line 926 andblock 928, the operator turns on the control feature by actuation ofon/off switch 180′ which, in turn, will cause the illumination of greenLED 182′. Next, as represented at line 930 and block 932 the operatormay select the duty cycles for activating the heater component and themagnetometer. While these intervals may be factory set, the operator maycarry out the selection by utilizing switch function 184′. The procedurecontinues as represented at line 934 and block 936 wherein the operatorselects the extent of travel of the table or platform 52′ or acorresponding chair-type support. That selection is made by operatoractuation of up/down switches 194′ while observing any correspondinglocus of travel value shown at display 196′. The program then continuesas represented at line 938 which extends to block 940 providing for theacquisition of the enabling voltage value of the motor control 78′.Following such acquisition, as represented at line 942 and block 944, adetermination is made as to whether that enabling voltage V_(mc) isgreater than or equal to three volts. If the determination at block 944is that the enabling voltage of the table control is not adequate, thenas represented at line 946 and block 948, an error message is displayedat the display 204′. The error, in general will indicate that thecontrol leads 84′ from the oscillation system are not properly attachedto the console 112′. The program then continues as represented at line950 and block 952 wherein the display 204′ outputs a display prompt, towit: “check the lead/cable attachment”. The program then reverts to line938 as represented at line 954.

In the event of an affirmative determination with respect to the queryposed at block 944, then as represented at line 956 and block 958 greenLED 210′ is illuminated and the procedure continues as represented atline 960 and block 962. In this regard, the operator carries out what ineffect is a “check run” of the oscillation of platform 52′. This checkis initiated by actuating button switch 198′. As the patient supportassemblage 54′ is activated, the procedure then evaluates the status ofthe magnetometer 104′. Accordingly, as represented at line 956 and block958 the magnetometer 104′ is turned on and the system acquires its onand continuity status information. The program then continues asrepresented at line 968 and block 970 wherein a determination is made asto whether the status of the magnetometer 104′ is ok. In this regard,the peak-to-peak variation of the magnetometer output voltage, V_(MO) iscompared with a reference, V_(FM). Where that condition obtains, thenthe enablement signal V_(C) is generated. This signal must be greaterthan or equal to three volts d.c. to be representative. In the eventthat the magnetometer status is not ok, then as represented at line 972and block 974 an error condition is displayed at display 204′ indicatingthat the magnetometer probe cable 108′ or cable 114′ to console 112′ isnot properly attached. The program then continues as represented at line976 and block 978 to display the prompt to the operator to check themagnetometer cable attachments. The program then returns as representedat line 980 to line 968.

Where the query posed at block 970 is responded to in the affirmative,then as represented at line 982 and block 984, green LED 212′ at console112′ is illuminated and the program continues as represented at line 986and block 988. At this juncture in the procedure, the operator will bepositioning the magnetometer probe 106′ as close as practical to thestent. This positioning will involve orientation of that probe toachieve a maximum magnetometer signal change with the oscillations ofthe platform 52′. The program then continues as represented at line 990.Line 990 extends to block 991 providing for the termination of the testrun of the support assemblage 54′. This is carried out by operatoractuation of the stop button switch 202′ on console 112′. The procedurecontinues as represented at line 992 and block 993 which provides foroperator selection of both therapy duration commencing with theattainment of setpoint temperature, T_(SP), and the maximum allottedtime to attain that temperature, T_(SP). Selection is carried out byactuation of switches 190′ and 191′ in conjunction with the readoutprovided at display 192′ (FIG. 41).

As represented at line 994 and block 996, the ACF heating assembly 94′is turned on, and as provided at line 998 and block 1000 a query isposed as to whether the ACF heating unit is enabled both by thedevelopment of a requisite on voltage level, V_(RF) as being greaterthan or equal to three volts and the presence of the earlier-describedmagnetometer signal V_(c) as being greater than or equal to three volts.If those ANDed conditions are not met, then as represented at line 1002and block 1004 an error visual cue is displayed at display 204′indicating that the control leads 102′ are not properly connected to thecontrol console 112′. The program then continues as represented at line1006 and block 1008 to display a prompt advising the operator to turnoff the ACF heating unit and the cable attachment 102′ extending to theconsole 112′. The program then reverts to line 994 as represented atline 1008.

Where the query posed at block 1000 results in an affirmativedetermination, then as represented at line 1012 and block 1014, greenLED 211′ is illuminated at console 112′ and the program continues asrepresented at line 1016. Line 1016 extends to the query posed at block1018 determining whether the duration for therapy and the maximum timeallocated to reach T_(SP) have been set to correct and intended values.Both intervals are set by the operator, employing the up/down switches190′ and election switch 191′ in conjunction with display 192′ onconsole 112′. The discussion associated with FIGS. 42 and 43 maybe-recalled with respect to the selection of therapy duration as to itsfunction in providing a temperature controlled dispersion ofchemotherapeutic or other release agents. One or more levels ofpredetermined Curie transition temperatures may be utilized inconjunction with a thermotherapy for restenosis per se and an adjunctdispersion of chemotherapeutic release agents. Where the therapyduration or time to T_(SP) intervals are incorrect, then as representedat line 1020 and block 1022 appropriate adjustment at control switches190′ and 191′ is made and the program reverts to line 1016 asrepresented at line 1024.

Where the query posed at block 1018 is responded to in the affirmative,then as represented at line 1026 and block 1028 a determination is madeas to whether the therapy time elapsed indicates zero minutes. Thisreadout is provided at console 112′ at display 222′. In the event thatdisplay does not register zero minutes, then as represented at line 1030and block 1032, reset button switch 224′ is actuated and the programcontinues as represented at lines 1034 and 1036. Therapy time elapsedhaving been set at zero, the procedure continues as represented at line1036 and block 1038. Block 1038 reflects the activity of controller 240(FIG. 8B) in carrying out a determination that the conditionsestablished by the illumination of LEDs 210′-212′ at console 112′ havebeen satisfied and the system now is ready to commence the thermotherapymode. In the event that the ready check fails, then as represented atline 1040 and block 1042, an error cue is published at display 204′ and,as represented at line 1044 and node A the program reverts to line 938to again consider the ready checks.

In the event the query posed at block 1038 results in an affirmativedetermination, then as represented at line 1046 and block 1048hyperthermia therapy is commenced with the operator actuation of thestart therapy button switch 220′ at console 112′. With this actuation,as represented at line 1050 and block 1052, the green LED 213′indicating that therapy is in progress at console 112′ is illuminatedand the procedure continues as represented at line 1054 to the querypresented at block 1056. Therapy being underway, the program determineswhether or not the, stop therapy button switch 226′ at console 112′ hasbeen actuated. In the event that such an actuation occurred, then asrepresented at line 1057 and block 1059, the ACF heating assembly 94′ isturned off as well as the motor control circuit 78′ of the supportassemblage 54′. As a visual cue that the therapy is stopped, red LED228′ is illuminated and, correspondingly, green LEDs 200′ and 213′ arede-energized. The procedure then continues as represented at line 1060and block 1061 wherein the operator determines whether or not thetherapy mode is to be resumed. Where resumption is intended, then asrepresented at line 1060 and block 1061 the start therapy button switch220′ is actuated at control console 112′ which, in turn, causes theturning off of red LED 228′ and the turning on of green LEDs 200′ and213′. This automatically restarts the platform 52′ oscillation and there-activation of the ACF heating assembly 94′. The program thencontinues as represented at line 1064 which extends to line 1050. Wherethe query posed at block 1061 results in a determination that therapy isnot to be resumed, then as represented at line 1065 and node 1066, thetherapy is ended.

Returning to block 1056, where a determination has been made that thestop therapy switch 226′ has not been actuated, then as represented atline 1067 and block 1068 a determination is made as to whether thetarget or setpoint temperature, T_(SP) has been reached. This targettemperature has been discussed in conjunction with dashed line 142 ofFIG. 7. Where the target or setpoint temperature has been reached, thenas represented at line 1070 and block 1072, a query is made as towhether the time to setpoint temperature, T_(SP) has been reached or haselapsed before the setpoint temperature itself has been reached. In theevent that it has not, then as represented at line 1074 and block 1076,a start of timing of duration of treatment or the commencement of acontinuation of that therapy timing is effected. In the latter regard,should the stop therapy switch have been actuated and then therapyresumed as represented at block 1063, then timing will resume from thepoint where it had been interrupted.

The procedure then continues as represented at line 1078 and block 1080providing for the illumination of green LED 215′ on console 112′□.□ Theprogram then continues as represented at line 1082. Where the inquiryposed at block 1068 results in a negative determination, then asrepresented at line 1084 the program reverts to line 1082.

Line 1082 extends to the query posed at block 1086 wherein adetermination is made as to whether the therapy time elapsed has reachedthe value of the preset therapy duration. Where that is not the case,then as represented at line 1088 and block 1090, the time elapsedreadout 222′ is updated and the program reverts as represented at line1092 and node B to line 1054.

In the event the query posed at block 1086 results in an affirmativedetermination, then, as represented at line 1094 the therapy iscompleted and the procedure continues as represented at line 1094 andblock 1108. Returning to the query at block 1072, where an affirmativedetermination has been made that the time to setpoint has elapsed beforesetpoint temperature is reached, then an error condition obtains and isrepresented at line 1096 and block 1098, an error is displayed at 204′on console 112′ and the program reverts to line 1094 as represented atline 1100. Line 1194 extends to block 1108 which provides for thedeactivation of the active components of the system. In this regard, theACF heating assembly 94′ is deactivated as is the magnetometer assembly104′. Control circuit 78′ for the platform support assembly 54′ isdeactivated. Therapy complete green LED 214′ is illuminated and greenLED 213′ representing therapy in progress is de-energized. The programthen continues as represented at line 1110 and block 1112 whereinpertinent data representing the procedure parameters is recorded. It maybe recalled that this data can be displayed at display 204′ by theactuation of button switch 206′. The procedure then continues asillustrated at line 1114 extending to node 1116 representing a therapyended stage.

In the embodiments heretofore described, the patient has been supportedupon a moveable platform or chair for the purpose of deriving a relativemovement between the temperature sensor components and the magnetometerpick-up. However, this relative movement can be dispensed with, forexample, through the utilization of an array of magnetometer pick-upswhich is arranged as such that certain of the pick-ups within the arraywill intercept magnetic field flux lines affected by the sensorcomponents while other somewhat adjacent pick-ups within the array willintercept magnetic field lines which are unaffected by a sensorcomponent, i.e., the field lines will not have intercepted thosecomponents. Referring to FIG. 51, schematic representation of such anembodiment is provided. Because of the similarity of the embodiment ofFIG. 51 with that earlier-described in connection with FIG. 5, items ofcommonality between these figures are identified in FIG. 51 with thesame numeration as FIG. 5 but in double primed fashion. Removal of theoscillatory platform will be seen to result in a corresponding removalof certain control functions. In the figure, the patient 50′ is shown ina supinate position on a stationary horizontal platform 1120. Otherpatient support structures may be employed such as modified chairs andthe like. The target tissue volume of interest is again representedinternally within the body of the patient 50″ by a symbolicallyrepresented dashed boundary 90″. Within this boundary 90″ there is shownat least one temperature sensor or sensor/heater implant configuredaccording to the invention as represented schematically at 92″. Asbefore, the implant 92″ is untethered, having no electrical leadsextending exteriorly of the patient 50″.

Heating of the region of interest 90″ under thermotherapy conditionsand, in particular, hyperthermia conditions is provided from thealternating current field heating assembly represented at block 94″.Line power input is represented as being directed to the assembly 94″ atarrow 96″. Substantially focused radiative heating is provided from theACF heating assembly 94″ by a typical coil-implemented heating componentrepresented at 98″ which is positioned in close proximity to the skin ofpatient 50″ in the vicinity of a predetermined and earlier markedlocation of the target tissue volume 90″. Association of the component98″ with the heating assembly 94″ is represented schematically by linepair 100″. Preferably, the component 98″ may be associated with aninduction heating assemblage operating at a lower frequency within thegenerally identified radio frequency range.

Now looking to the magnetometer-based detection of the earth magneticfield disturbances evoked by the state of permeability of the sensorcomponent at implant 92″, a magnetometer control assembly is representedat block 1122. Assembly 1122 is of a multichannel variety and performsin conjunction with the remotely disposed pick-up or multichannel arrayor probe 1124, the channels of which are oriented for discerning and/ordifferentiating magnet field flux lines as they may be affected by theimplant or implants at 92″. In effect, the magnetometer sensor array1124 provides for the measurement of a two-dimensional pattern ofmagnetic field strength allowing the change in the field strengthpattern to be detected as the ferromagnetic sensor 92″ changes from amagnetic to a non-magnetic state—a change which occurs over a narrowtemperature range (FIG. 2) around the intrinsic Curie temperature of theferromagnetic material selected. The association of the multichannelprobe or pick-up 1124 with the assembly 1122 is represented at cable1126. Assembly 1122 is seen receiving line power as represented by arrow110″ and is controlled and provides outputs to a modified consolemounted control assembly represented generally at 112″ as indicated atarrow 114″. It may be noted that the control assembly 112″ does notincorporate the earlier-described table/chair control features, however,all other features described in connection with FIGS. 5, 8A and 8B areretained. While the magnetometer assembly 1122 may perform inconjunction with a synthetically generated magnet field, for the instantembodiment, the earth's magnetic field is employed in conjunction withthe sensing approach. As before, the magnetometer assemblies for theinstant applications generally will be configured in the manner offluxgate sensors.

While the tissue heating function of assembly 94″ may be carried outsimultaneously with the temperature monitoring function of themagnetometer assembly 1122, such coincident operation necessarilyrequires that the monitoring function be effectively shielded orprotected from electromagnetic interference. An approach to avoidingthis interference is to intermit the operation of these assemblies inthe manner described in connection with FIG. 7. In this regard, theheater assembly 94″ is activated for the earlier-described interval δt₁and the magnetometer 1122 is enabled subsequent to that time incrementfor an interrogation interval δt₂. Ranges for these delta values are setforth in Table 1.

The interactive control functions of the control console 112″ areessentially identical to those described in connection with FIG. 5.Applied power levels are set by the user in conjunction with theapparatus 94″ itself. However, the controls at console 112″ then look toa timing parameter for correctly establishing the energy quantum ofthermotherapeutic application. Console 112″ is powered-on with a keyswitch 180″, such a power-on condition being represented by theillumination of green LED 182″. While typically established by themanufacturer of the control at console 112″, the duty cycles for theapplication of power or heat in the quiescent interval immediatelyfollowing such heat application is shown as being electable by the user.Insertion of this operational criteria is provided at the switchcombination shown generally at 184″. The switches 184″ include a heatinterval input 186″ and a corresponding sensor interrogation intervaladjustment function 188″. As noted above, see the time interval rangesfor δ_(t1) and δ_(t2) set forth in Table 1. With the duty cyclesestablished, next, the total duration for a given therapy is insertedinto the system utilizing up/down momentary depression switches asrepresented generally at 190″ in combination with election switch 191″and a switch display 192″, the latter feature providing a visiblyperceptible visual time selection, for example, in minutes. Switch 191″provides for selection of Therapy Duration (TD) from the attainment ofsetpoint temperature and maximum time allocated for reaching T_(SP)(TTT_(SP)).

In the course of setting up a therapy, certain associatedinterconnections will be made by the operator. The control systemrepresented by the console 112″ will respond to errors in that setupprocedure and provide visual indicia as to error involved andadditionally will provide a prompt as to corrective action to be taken.That information is provided at visual display 204″. Display 204″ alsowill provide a display of pertinent data concerning a completed therapyby operator actuation of momentary on switch 206″. That data also willbe recorded automatically in data log memory.

During the course of the setup and subsequent therapeutic operation ofthe system, an array of visual indicators as to the progress of theprocedure as represented generally at 208″ will provide confirmationaloutputs. In this regard, the illumination of green LED 211″ indicatesthat an ACF heating assembly 94. switch located at that unit has beenthrown to apply power. Additionally, its illumination indicates that themagnetometer control 1122 monitoring features have indicated thatpeak-to-peak variations of its control voltages are greater than areference value. LED 212″, when illuminated, provides for an indicationthat magnetometer 1122 is in a ready condition. In this regard, itspower-on switch will have been actuated to an on condition and itspeak-to-peak voltage will have equaled or exceeded a reference voltagevalue. Next, green LED 213″ is illuminated to provide an indication thattherapy is in progress, and green LED 214″, when illuminated, indicatesthat the therapy duration now has been reached and therapy is completed.Finally, green LED 215″ is illuminated to indicate that the targettemperature or setpoint temperature T_(SP) (FIG. 7) has been reached andtherapy duration commences to be timed out. Once setpoint temperature isreached, this LED 215″ will remain illuminated until the end of thetherapy or upon stopping of the therapy.

Therapy is commenced with the user actuation of the momentary on starttherapy switch 220″. During the interval of the therapy, the timeelapsed for therapy commencing with the attainment of setpointtemperature, T_(SP) is indicated at display 222″. That display may bereset to zero by actuation of momentary on switch 224″. If, during theprogress of the therapeutic performance of the system, the operatordeems it advisable to stop the therapy, then the stop therapy switch226″ is actuated momentarily and the therapy stop red LED 228″ isilluminated.

Concerning the general operation of the control function at console112″, it may be noted that unless the checking logic of the controlsystem will have functioned to carry out the illumination of the “ready”LED (s) 211″-212″, then the start therapy switch 220″ will not beenabled. In general, error and prompt messages will remain at thedisplay 204″ where the start-up conditions are not satisfied. Thecontrol system represented at console 112″ is configured as describedabove in connection with FIGS. 8A and 8B with the earlier-noted tableoscillation related functions deleted.

FIGS. 52A-52F present a block diagrammatic representation of procedureof the invention associated with the arrangement of FIG. 51.

Looking to FIG. 52A, the procedure is seen to commence at node 1130 andline 1132 leading to the determinations set forth at block 1134. Thosedeterminations provide for the election of target therapy temperature(s)for instance, for hyperthermia with (HSP) induction and susceptibilityto adjunct therapies such as chemotherapy, i.e., release agentdispersion by heat activation, boney tissue mending or the like. Theprocedure then continues as represented at line 1136 and block 1138providing for the user selection of implant sensor (s) thermal responsesbased upon the elected target therapy setpoint temperature ortemperatures. With temperature elections having been made and sensorcomponent/heater component configuration determined, then as representedat line 1140 and block 1142 the power level for the ACF heating assembly94″ is selected and set by the user. Where the therapy will include thestimulation of induction of heat shock proteins, then, as represented atline 1144 and block 1146 the user may evolve a maximum therapy durationat elected target temperature or temperatures to establish an energyquanta of thermal application to the target tissue volume. The electionof such maximum values is made to avoid generation of temperatures ortemperature in time conditions falling above critical curves as at 24described in connection with FIG. 3 and to maximize stimulation for aninduction of HSPs. The procedure then continues as represented at line1148 and block 1150 providing for the administration of general or localanesthetic agent as required. Then, as represented at line 1152 andblock 1154, using one or more of the above-discussed imaging techniques,the implant is inserted into or adjacent to the target tissue volume ofthe patient utilizing an implant device, for example, as discussed inconnection with FIGS. 32 and 33. As part of this procedure, the exteriorof the patient's body is marked to indicate the closest location of theimplant or implants so as to facilitate the positioning of the radiativeheating coil or antenna as well as to orient the pick-up structure 1124of the magnetometer assembly 1122. As discussed above, the implants maybe installed as part of an intraoperative-surgical procedure.

Next, the method provides a confirmational procedure as represented atline 1156 and block 1158 wherein the imagining and other suchinstrumentation are used for purposes of ascertaining if the implantsare in the proper location with respect to the target tissue. Should theimplant positioning not be appropriate, then as represented at loop line1160, the method reverts to the procedure described in connection withblock 1154. Upon an affirmative determination with respect to the queryposed at block 1158, then as represented at line 1162 and block 1164 thepatient is positioned on the treatment support 1120 so that the earlierlocated marker or outline on the surface of the patient is visible forthe next step in the procedure. That step provides for locating the ACFheating coil or microwave antenna as well as the magnetometer probe 1124at the proper locations with respect to the skin of the patient. Theprocedure then continues as represented at line 1166 and block 1168wherein, guided by the marker at the skin surface of the patient, theheating coil 98″ or microwave antenna is positioned as close aspractical with respect to the skin of the patient to the sensor/heaterimplant(s). The method then continues as represented at line 1170extending to block 1172 providing for turning on control console 112″ byactuating switch 180″ to, in turn, illuminate green LED 182″. Then, asrepresented by line 1174 and block 1176, the operator selects the dutycycles. It may be recalled that duty cycle ranges, δt₁ and δt₂ are setforth in Table 1. As described in conjunction with FIG. 51, duty cycleelection is undertaken with switch function 184″. Next, as representedby line 1178 and block 1180 the procedure evaluates the status of themagnetometer. In this regard, the magnetometer is turned on and thesystem acquires its on and continuity status information. The programthen continues as represented at line 1182 and block 1184 wherein adetermination is made as to whether the status of the magnetometer 1122is ok. In this regard, the peak-to-peak variation of the magnetometeroutput voltage, V_(MO) is compared with a reference, V_(FM). Where thatcondition obtains, then the enablement signal, V_(c) is generated. Thissignal must be greater than or equal to, for example, three volts d.c.to be representative. In the event that the magnetometer status is notok, then as represented at line 1186 and block 1188, an error conditionis displayed at display 204″ indicating that the magnetometer probecable 1126 or the cable 114″ to console 112″ is not properly attached.Continuing the program, as represented at line 1190 and block 1192 aprompt is displayed to the operator to check the magnetometer cableattachments. The program then returns as represented at line 1194 toline 1178.

Where the query posed at block 1184 is responded to in the affirmative,then as represented at line 1196 and block 1198 green LED 212″ atconsole 112″ is illuminated and the program continues as represented atline 1200 and block 1202. At this juncture in the procedure, theoperator will be positioning the magnetometer probe 1124 as close aspractical to the implant(s) in order to obtain a maximum magnetometersignal channel differentiation.

The procedure continues as represented at line 1203 and block 1204 whichprovides for operator selection of both therapy duration commencing withthe attainment of setpoint temperature, T_(SP), and the maximum allottedtime to attain that temperature, T_(SP). Selection is carried out byactuation of switches 190″ and 191″ in conjunction with the readoutprovided at display 192″. (FIG. 51).

The ACF heating assembly actuation next is addressed as represented atline 1205 and block 1206 providing that the ACF heating assembly 94″ isturned on and, as represented at line 1208 and block 1210, a query isposed as to whether the ACF heating unit is enabled both by thedevelopment of a requisite voltage level, V_(RF) as being greater thanor equal to, for example, three volts and the presence of theearlier-described magnetometer signal V_(c) as being greater than orequal to, for example, three volts. If those ANDed conditions are notmet, then as represented at line 1212 and block 1214 an error visual cueis displayed at display 204″ indicating that the control leads 102″ arenot properly connected to the control console 112″. The program thencontinues as represented at line 1216 and block 1218 to display a promptadvising the operator to turn off the ACF heating unit and check thecable attachment 102″ extending to the console 112″. The program thenreverts to line 1204 as represented at line 1220.

Where the query posed at block 1210 results in an affirmativedetermination, then as represented at line 1222 and block 1224, greenLED 211″ is illuminated and the program continues as represented at line1226. Line 1226 extends to the query posed at block 1228 determiningwhether the duration for therapy and maximum time to achieve setpointtemperature have been set to correct and intended values. The times areset by the operator employing the up/down switches 190″ in conjunctionwith election switch 191″ and display 192″ on console 112″. It may berecalled that for such activities as the temperature controlleddispersion of release agents (see FIGS. 42, 43), one or more levels ofpredetermined Curie transition temperatures may be utilized inconjunction with a corresponding sequence of sensor component containingimplants. In the latter aspect, such therapy may involve maintenance ofthe quantum of thermal energy below critical curves as at 24 describedin connection with FIG. 3. Where the therapy duration is incorrect, thenas represented at line 1230 and block 1232 appropriate adjustment of thecontrol switches 190″ and 191″ is made and the program reverts to line1226 as represented at line 1234.

Where the query posed at block 1228 is responded to in the affirmative,then as represented at line 1236 and block 1238 a determination is madeas to whether the therapy time elapsed indicates zero minutes. Thisreadout is provided at console 112″ at display 222″. In the event thatthis display does not register zero minutes, then as represented at line1240 and block 1242, reset button switch 224″ is actuated and theprogram continues as represented at lines 1244 and 1236. With thetherapy time elapsed set at zero, the procedure continues as representedat line 1246 and block 1248. Block 1248 reflects the activity ofcontroller 240 (FIG. 8B) in carrying out a determination that theconditions established by the illumination of LEDs 211″- 212″ at console112″ have been satisfied and the system now is ready to commence athermal therapy mode. In the event the ready check fails, then asrepresented at line 1250 and block 1252 an error cue is published atdisplay 204″ and, as represented at line 1254 and node A the programreverts to line 1178 to again consider the ready checks. In this regardnode A and line 1254 reappears adjacent line 1178.

In the event the query posed at block 1248 results in an affirmativedetermination, then as represented at line 1256 and block 1258thermotherapy which may comprise hyperthermia therapy commences with theoperator actuation of the start therapy button switch 220″ at console112″. With this actuation, as represented at line 1260 and block 1262,the green LED 213″ indicating that therapy is in progress at console112″ is illuminated and the procedure continues as represented at line1264 to the query at block 1266. Therapy being underway, the programdetermines whether or not the stop therapy button switch 226″ at console112″ has been actuated. In the event that such an actuation occurred,then as represented at line 1267 and block 1268, the AC Field heatingassembly is turned off. As a visual cue that the therapy is stopped, redLED 228″ is illuminated and, correspondingly, green LED 213″ isde-energized. The procedure then continues as represented at line 1269and block 1270 wherein the operator determines whether or not thetherapy mode is to be resumed. In the event that it is to be so resumed,then as represented at line 1271 and block 1272, in order to resume thetherapy mode for the duration of the unlapsed therapy, the start therapyswitch 220″ is actuated at control console 112″ which, in turn, causesthe turning off of red LED 228″. This automatically activates the ACFheating assembly 94″. The program then continues as represented at line1273 which extends to line 1260.

Where the query posed at block 1270 results in a determination thattherapy is not to be resumed, then as represented at line 1274 and node1275 the therapy is ended.

Returning to block 1266, where a determination has been made that thestop therapy switch 226″ has not been actuated, then as represented atline 1276 and block 1277, a determination is made as to whether thetarget or setpoint temperature, T_(SP), has been reached. This targettemperature has been discussed in conjunction with dashed line 142 inconnection with FIG. 7. Refer additionally to the ranges provided inconjunction with T_(heater) set forth in Table 1. When the target orsetpoint temperature has been reached, then as represented at line 1278and block 1280, the program determines whether the maximum time assignedfor attaining setpoint temperature has been reached before the setpointtemperature has been attained. Where that conflict is not at hand, thenas represented at line 1281 and block 1282, the therapy duration timeoutis started or its earlier commencement is continued following theactuation of the start therapy button as discussed in connection withblock 1272. The program then continues as represented at line 1284 toblock 1285 providing for the illumination of the green LED 215″ onconsole 112″. The program continues as represented at line 1286. Wherethe target temperature has not been reached then, as represented atlines 1287 and 1286 the program continues to the query posed at block1288. That query determines whether or not the therapy time elapsed asdisplayed at display 222′ on console 112″ has reached a therapy durationvaluation. In the event that it has not, then as represented at line1290 and block 1292 the time elapsed display 222″ is updated and, asrepresented at line 1294 and node B the program reverts to line 1264.Node B reappears with line 1294 adjacent line 1264. Where the therapytime elapsed corresponds with the therapy duration time, then theprogram continues as represented at line 1298. Returning to block 1280,where the maximum time assigned for the system to reach setpointtemperature has elapsed prior to a setpoint temperature being reached,then as represented at line 1300 and block 1302, an error cue isdisplayed and the program continues as represented at lines 1304 and1298. Line 1298 extends to block 1320 which provides for thedeactivation of the active components of the system. In this regard, theACF heating assembly 94″ is deactivated as is the magnetometer assembly1122. Therapy complete green LED 214″ is illuminated and green LED 213″representing therapy in progress is de-energized. The program thencontinues as represented at line 1322 and block 1324 wherein pertinentdata for the procedure parameters is recorded. It may be recalled thatthis data can be displayed at display 204″ by the actuation of buttonswitch 206″. The procedure then continues as illustrated at line 1326extending to node 1328 representing a therapy ended stage.

The utilization of an array of magnetometer pick-ups in the mannerdescribed in connection with FIG. 51 also finds applicability to thetreatment of restenosis as discussed earlier in connection with FIGS. 41et seq. Referring to FIG. 53, patient 770 reappears from FIG. 41 beingsupported in a supinate position from stationary platform 1120 whichreappears from FIG. 51. The heart of patient 770 is shown at 772 alongwith a coronary artery 752 incorporating a stent formed according to theinvention at 748 (FIGS. 39-40). Control console 112″ reappears from FIG.51 as does the associated ACF heating assembly 94″. Substantiallyfocused heating is provided from the heating assembly 94″ by acoil-implemented heating component represented at 98″ which ispositioned in close proximity to the skin of the patient 770 adjacentthe stent 748. As before, the component 98″ preferably is associatedwith an induction heating assemblage operating at a relatively lowerfrequency with respect to the generally identified radiofrequency range.Magnetometer 1122 in combination with cable 1126 and pick-up array 1124reappear from FIG. 51. As described above in connection with FIG. 51,assembly 1122 is of a multichannel variety and performs in conjunctionwith a corresponding multichannel array or probe 1124, the channels ofwhich are oriented for discerning and/or differentiating magnetic fieldflux lines as they may be affected by the sensors affixed to the stent748. Array 1124 and associated multichannel magnetometer 1122 providefor the measurement of a two-dimensional pattern of magnet fieldstrengths allowing the change in the field strength pattern to bedetected as the ferromagnetic sensor(s) at the stent 748 changes from amagnetic to a non-magnetic state, a change which occurs over a narrowtemperature range (FIG. 2) around the intrinsic Curie temperature of theferromagnetic material selected. As before, it may be noted that thecontrol assembly 112″ does not incorporate the earlier-describedtable/chair control features, however, all the other features describedin connection with FIGS. 5, 8A and 8B are retained. For the instantembodiment, the earth's magnetic field is employed in conjunction withthe temperature sensing approach.

The discourse now turns to the procedure and control associated with theembodiments described in connection with FIG. 53 as well as FIGS. 39-40and 42-49. Looking to FIG. 54A the initial phase of the procedureinvolves the positioning of a stent transluminally within the patient.That stent typically will be positioned as part of percutaneoustransluminal coronary angioplasty (PTCA). For the instant method, thestent will incorporate an integral temperature sensing system and mayfurther incorporate heat activatable drug components. The stentpositioning phase involves the administration of a general or localanesthetic agent as indicated at block 1336. Then, as represented atline 1338 and block 1340 the stent with integral sensor is positionedwithin the patient's blood vessel at the targeted location, and,typically utilizing balloon procedures, the stent is deployed such thatit is securely imbedded at the intima of the blood vessel. Then thedelivery catheter is removed from the patient and, as represented atline 1342 and node 1344 the stent positioning phase will have ended.Subsequent to this implantation restenosis may arise within a timeinterval that may range from weeks to years.

As an alternate to the procedure thus far described, the secondary stentapproach described in conjunction with FIGS. 46-49 may be carried out asrepresented at block 1346. With this procedure, a stent which hasalready been implanted is supplemented with temperature sensorcomponents according to the invention by catheter placement andexpansion within that preexisting stent.

Subsequent to the stent positioning phase the patient will be monitoredfor the occurrence of clinically significant restenosis. As representedat block 1348 such checks may be carried out, for instance, usingangiography, diagnostic ultrasound, x-ray, or MRI techniques. Theprocedure then continues as represented at line 1350 and block 1352,where a query is presented as to whether or not evidence of restenosisis present. In the event that it is not, then as represented at line1354, block 1356 and line 1358, such checks are continued, the patient'scardiac/circulatory function being monitored on a periodic basis. Whereevidence of restenosis does exist, then as represented at line 1360thermotherapy according to the invention is commenced. Looking to block1362 a marker initially is placed on the skin of the patient at alocation selected for aiding in the positioning of the magnetometerprobe array 1124 and the inductive heater coil 98″. As represented atline 1364 and block 1366, the patient is positioned on the stationarytable or chair as at 1120 so that the skin located marker is clearlyvisible for the noted coil and probe orientation. Then, as representedat line 1368 and block 1370 the heating coil positioning mode iscommenced. In this regard, using the marker at the surface of thepatient, the heating coil 98″ is located as close as practical to thelocation of the stent/sensor implant. Then, as indicated by line 1372and block 1374, the operator turns on the control console 112″ byactuation of on/off switch 180″ which, in turn, will cause theillumination of green LED 182″. Next, as represented at line 1376 andblock 1378 the operator may select the duty cycles for activating theheater assembly and the magnetometer. While these intervals may befactory set, the operator may carry out selection by utilizing switchfunction 184″. It may be recalled that duty cycle ranges δt₁ and δt₂ areset forth in Table 1.

Next, as represented by line 1380 and block 1382 the procedure evaluatesthe status of the magnetometer. In this regard, the magnetometer 1122 isturned on and the system acquires its on and continuity statusinformation. The program then continues as represented at line 1384 andblock 1386 wherein a determination is made as to whether the status ofthe magnetometer 1122 is ok. In this regard, the peak-to-peak variationof the magnetometer output voltage is compared with a reference, V_(FM).Where that condition obtains, then the enablement signal, V_(c) isgenerated. This signal must be greater than or equal to, for example,three volts d.c. to be representative. In the event that themagnetometer status is not ok, then as represented at line 1388 andblock 1390 an error condition is displayed at display 204″ indicatingthat the magnetometer probe cable 1126 or the cable 114″ to console 112″is not properly attached. The program then continues as represented atline 1392 and block 1394 to display a prompt to the operator to checkthe magnetometer cable attachments. The program then returns asrepresented at line 1396 to line 1380.

Where the query posed at block 1386 is responded to in the affirmative,then as represented at line 1398 and block 1400 green LED 212″ atconsole 112″ is illuminated and the program continues as represented atline 1402 and block 1404. At this juncture in the procedure, theoperator will be positioning the magnetometer array-type probe 1124 asclose as practical to the stent 748 in order to obtain a maximummagnetometer signal channel differentiation.

The procedure continues as represented at line 1406 and block 1407 whichprovides for operator selection of both therapy duration commencing withthe attainment of setpoint temperature, T_(SP), and the maximum timeallotted to attain that temperature. Selection is carried out byactuation of switches 190″ and 191″ in conjunction with the readoutprovided at display 192″ (FIG. 53).

The ACF heating assembly 94″ actuation next is addressed as representedat line 1408 and block 1409. Upon turning on the heating unit, asrepresented at line 1410 and block 1412 a query is posed as to whetherthe ACF heating unit is enabled both by the development of a requisitevoltage level, V_(RF) as being greater than or equal to, for example,three volts and the presence of the earlier-described magnetometersignal V_(c) as being greater than or equal to, for example, threevolts. If those ANDed conditions are not met, then as represented atline 1414 and block 1416 an error visual cue is displayed at display204″ indicating that the control leads 102″ are not properly connectedto the control console 112″. The program then continues as representedat line 1418 and block 1420 to display a prompt advising the operator toturn off the ACF heating unit and check the cable attachment 102″extending to the console 112″. The program then reverts to line 1408 asrepresented at line 1422.

Where the query posed at block 1412 results in an affirmativedetermination, then as represented at line 1424 and block 1426, greenLED 211″ is illuminated and the program continues as represented at line1428. Line 1428 extends to the query posed at block 1430 determiningwhether the duration for therapy and the maximum time to achievesetpoint temperature have been set to correct and intended values. Thesetimes are set by the operator employing the up/down switches 190″ andelection switch 191″ in conjunction with display 192″ on console 112″.It may be recalled that for such activities as the temperaturecontrolled heating dispersion of chemotherapeutic and the like releaseagents as discussed in connection with FIGS. 42 and 43, one or morelevels of predetermined Curie transition temperatures may be utilized inconjunction with a corresponding sequence of stent containing sensorcomponents. Where the therapy duration is incorrect, then as representedat line 1432 and block 1434 appropriate adjustment of the control andelection switches 190″ and 191□′□′ is made and the program reverts toline 1428 as represented at line 1436.

When the query posed at block 1430 is responded to in the affirmative,then as represented at line 1438 and block 1440 a determination is madeas to whether the therapy time elapsed indicates zero minutes. Thisreadout is provided at console 112″ at display 222″. In the event thatthis display does not register zero minutes, then as represented at line1442 and block 1444, reset button switch 224″ is actuated and theprogram continues as represented at lines 1446 and 1438. With thetherapy time elapsed set at zero, the procedure continues as representedat line 1448 and block 1450. Block 1450 reflects the activity ofcontroller 240 (FIGS. 8A-8B) in carrying out a determination that theconditions established by the illumination of LEDs 211″-212″ at console112″ have been satisfied and the system now is ready to commence athermotherapy mode. In the event the ready check fails, then asrepresented at line 1452 and block 1454 an error cue is published atdisplay 204″ and the program reverts as represented at line 1456 andnode, A. Node A reappears in FIG. 54B in conjunction with line 1458extending to line 1380. Accordingly, the program is reentered to againconsider the ready checks.

In the event the query posed at block 1450 results in an affirmativedetermination, then as represented at line 1460 and block 1462thermotherapy which may comprise hyperthermia therapy commences with theoperator actuation of the start therapy button switch 220″ at console112″. With this actuation, as represented at line 1464 and block 1466the green LED 213″ is energized indicating that therapy is in progressand the procedure continues as represented at line 1468 to the query atblock 1470. Therapy being underway, the program determines whether ornot the stop therapy button switch 226″ at console 112″ has beenactuated. In the event that such an actuation occurred, then asrepresented at line 1471 and block 1472, the AC field heating assemblyis turned off. As a visual cue that the therapy is stopped, red LED 228″is illuminated and, correspondingly, green LED 213″ is de-energized. Theprocedure then continues as represented at line 1473 and block 1474wherein the operator determines whether or not the therapy mode is to beresumed. In the event it is to be so resumed, then as represented atline 1475 and at block 1476 therapy is resumed for the remainingduration of unlapsed therapy or maximum time allotted to reach setpointtemperature, T_(SP), by actuating the start therapy switch 220″ atcontrol console 112″. This actuation, in turn, causes the turning off ofred LED 228″ and automatically activates the AC field heating assembly94″. The program then continues as represented at line 1477 whichextends to line 1464.

Where the query posed at block 1474 results in a determination thattherapy is not to be resumed, then as represented at line 1478 and node1479 the therapy is ended.

Returning to block 1470, where a determination has been made that thestop therapy switch 226″ has not been actuated, then as represented atline 1480 and block 1481, a determination is made as to whether thetarget or setpoint temperature T_(SP) has been reached. This targettemperature has been discussed in conjunction with dashed line 142 inconnection with FIG. 7. Refer additionally to the ranges provided inconjunction with T_(stent) set forth in Table 1. When the target orsetpoint temperature has been reached, then as represented at line 1482and block 1484, a query is made as to whether the maximum time allocatedto reaching setpoint temperature T_(SP) has elapsed before that setpointtemperature has been reached. In the event of a negative determination,then as represented at line 1486 and block 1488, the program starts orcommences continuation of the therapy duration. In this regard, therapyat setpoint temperature may have been underway within a proper timeformat before the actuation of the stop therapy switch as discussed inconnection with block 1470. On the other hand, the target temperaturehaving been reached, the therapy duration as elected by the operator maycommence at this point. The program then continues as represented atline 1490 and block 1492 which provides for the illumination of greenLED 215″ representing target temperature having been reached and theprogram continues as represented at line 1494. When the targettemperature has not been reached, then as represented at lines 1496 and1494, the program proceeds to query at block 1498. That query determineswhether or not the therapy time elapsed as displayed at display 222″ onconsole 112″ has reached a therapy duration valuation. In the event thatit has not, then as represented at line 1500 and block 1502 the timeelapsed display 222″ is updated and, as represented at line 1504 andnode B the program reverts to line 1468. Node B and line 1504 reappearadjacent line 1468. Where the query posed at block 1498 is answered inthe affirmative, then as represented at line 1506 and block 1522 thesystem enters a mode deactivating the active components of the system.In this regard, the ACF heating assembly 94″ is deactivated as is themagnetometer assembly 1122. Therapy complete green LED 214″ isilluminated and green LED 213″ representing therapy in progress isde-energized.

Where the query posed at block 1484 results in an affirmativedetermination that the allocated maximum time to reach setpoint haselapsed before that setpoint has actually been reached, then an errorcondition is at hand and is represented at line 1508 and block 1510, anerror condition is displayed at display 204″ and the program continuesas represented at lines 1512 and 1506 to the shutdown procedures asabove described at block 1522. The program continues as represented atline 1524 and block 1526 wherein pertinent data for the procedureparameters is recorded. It may be recalled that this data can bedisplayed at display 204″ by actuation of button switch 206″. Theprocedure then continues as illustrated at line 1528 extending to node1530 representing a therapy ended stage.

Returning to FIG. 53, another embodiment of the instant invention whichinvolves a stationary patient may be carried out through the utilizationof a moving sensor component. In particular, where the stent 748 iswithin a coronary artery adjacent to the heart 772 the stent and itsassociated temperature sensor will be caused to move by virtue of thebeating of heart 772. Accordingly, the magnetometer assembly and probedescribed respectively at 104′ and 106′ in connection with FIG. 41 maybe utilized as illustrated in phantom. A single channel magnetometer asdescribed at 94′ may be employed in this arrangement of a stationarypatient and moving stent/sensor combination.

The system and method thus far presented has utilized the earth'smagnetic field in conjunction with the temperature sensors andmagnetometer instrumentation. However, the magnetic field may be appliedutilizing an electromagnet. FIGS. 55 through 57 illustrate thisapproach. In FIG. 55, a multichannel magnetometer arrangement with apick-up array and a stationary patient support is employed in the mannerdescribed in connection with FIG. 51. Accordingly, the componentidentifying numeration is imported from that figure but in triple primedfashion. However, disposed about the implant region of interest 90′″ areelectromagnet poles 1540 and 1542 of an electromagnet assemblyrepresented generally at 1544. Control over the electromagnet 1544 isrepresented by the dual arrow 1546 extending to the control console112′″. Console 112′″ incorporates all of the components described inconnection with console 112″ shown in FIG. 51. However, the console maybe observed to incorporate a start electromagnet button switch 1548 anda corresponding stop electromagnet switch 1550. When the electromagnet1544 is in an energized or on state, a green LED 1552 is illuminated.Additionally within the LED array 208′″ there is interposed a greenelectromagnet ready LED 1554.

Looking to FIGS. 56A and 56B which should be considered in accordancewith the labeling thereon, the components earlier-described inconjunction with FIGS. 8A and 8B are reproduced but in triple primedfashion. The figure differs from FIGS. 8A and 8B in that the motorcontrol and patient support drive functions along with associated cueingand switching are removed and the electromagnet 1544 is now representedin block form with that same identifying numeration. In FIG. 56A theelectromagnet 1544 is shown interactively controlled as represented atarrow 1546 by an electromagnet control network represented at block1556. Block 1556 is shown interactively controlled from the controller240 as represented by arrow 1558. Control 1556 receives stop and startcommands as represented at arrows 1560 and 1562 extending tocorresponding switch blocks 1550 and 1548. FIG. 56B further reveals “EMready” LED 1554 being coupled for energization from controller 240″. asrepresented at arrow 1564. Similarly, the “EM on” LED 1552 isprogramably energized from controller 240′″ as represented at arrow1566.

Referring to FIGS. 57A-57G, a block diagrammatic representation of thecontrol and procedure is set forth for the embodiment employing amagnetic field generated by an electromagnet. The procedure commences inconnection with FIG. 57A at node 1580 and line 1582 leading to thedeterminations at block 1594. Those determinations provide for theelection of target therapy temperature (s), for instance, forhyperthermia with heat shock protein (HSP) induction stimulation.Additionally, the thermotherapy may be selected for combination withsuch adjunct therapies as radiation therapy and/or chemotherapy byrelease agent dispersion by heat activation. The procedure thencontinues as represented at line 1586 and block 1588 providing for theuser selection of implant sensor (s) thermal responses based upon theelected target therapy setpoint temperature or temperatures. Withtemperature elections having been made and sensor component/heatercomponent configurations determined, then as represented at line 1590and block 1592 the power level for the ACF heating assembly 94.. isselected and set by the user. For stimulating the induction of heatshock proteins, as represented at line 1594 and block 1596 the user mayselect a maximum therapy duration at elected target temperature ortemperatures to establish energy quanta of thermal application to thetarget tissue volume. An election of such maximum values is made toavoid generation of temperatures or temperature in time conditionsfalling above the critical curve as at 24 described in connection withFIG. 3. The procedure then continues as represented at line 1598 andblock 1600 providing for the administration of general or localanesthetic agent as required. Then, as represented at line 1602 andblock 1604, using one or more of the above-discussed imaging techniques,the implant is inserted percutaneously or intraoperatively into oradjacent to the target tissue volume of the patient utilizing an implantdevice, for example, as discussed in connection with FIGS. 32 and 33. Asin the earlier embodiments, the orientation of the implant may beconsidered, particularly where more than one is being employed.Additionally, as part of this procedure, the exterior of the patient'sbody is marked to indicate the closest location of the implant orimplants so as to facilitate the positioning of the ACF heating coil orantenna as well as to orient the pick-up structure of the magnetometer.

Next, the method provides a confirmational procedure as represented atline 1606 and block 1608 wherein imaging and other such instrumentationare used for the purpose of ascertaining if the implants are in theproper location with respect to the target tissue. Should the implantpositioning not be appropriate, then as represented at loop line 1610,the method reverts to the procedure described in connection with block1604. Upon an affirmative determination with respect to the query posedat block 1608, then as represented at line 1612 and block 1614 thepatient is positioned on the treatment support such as the table 1120 sothat the earlier-located marker or outline on the surface of the patientis visible for the next step in the procedure. Next, as represented atline 1616 and block 1618 the heating coil positioning mode ensueswherein the ACF heating coil or antenna is located at a proper locationwith respect to the skin of the patient. The procedure then continues asrepresented at line 1620 and block 1622 providing for turning on theconsole 112′″ (switch 180′″ illuminating green LED 182′″). Then, asrepresented by line 1624 and block 1626, the operator selects the dutycycles. It may be recalled that duty cycle ranges δt₁ and δt₂ are setforth in Table 1. As described in conjunction with the FIG. 53, dutycycle election is undertaken with switch function 184′″. Next, asrepresented by line 1628 and block 1630 electromagnet 1544 is turned onby momentarily pressing the start electromagnetic button switch 1548 onconsole 112′″. This will cause the green LED 1552 to become illuminated.The procedure then continues as represented at line 1632 and block 1634providing for acquiring the on and continuity status of theelectromagnet 1540. This information is derived as described inconjunction with block 1556 and controller 240′″ in FIG. 57A. With thisinformation at hand, then as represented at line 1636 and block 1638 adetermination is made as to whether the status of the electromagnet 1540is ok. In the event that it is not, then as represented at line 1640 andblock 1642 an error cue is displayed corresponding with a cable toconsole fault. Then, as represented at line 1644 and block 1646 a promptis published at display 204″. advising the operator to check the cable1546. The program then loops to line 1636 as represented at line 1648.In the event the query posed at block 1638 indicates that theelectromagnet 1540 is ok, then as represented at line 1650 and block1652, green LED 1554 on console 112′″ is illuminated. Next asrepresented at line 1654 and block 1656 the magnetometer 1122′″ isturned on and, as represented at line 1658 and block 1660, the systemacquires the on and continuity status of the magnetometer. The programthen continues as represented at line 1662 and block 1664 wherein adetermination is made as to whether the status of the magnetometer1122′″ is ok. In this regard, the peak-to-peak variation of themagnetometer output voltage, V_(MO) is compared with a reference,V_(FM). Where that condition obtains, then the enablement signal V_(c)is generated. This signal, for example, must be greater than or equal tothree volts d.c. to be representative. In the event that themagnetometer status is not ok, then as represented at line 1666 andblock 1668, an error condition is displayed at display 204″. indicatingthat the magnetometer probe cable 1126′″ or the cable 114′″ to console112′″ is not properly attached. The program then continues asrepresented at line 1670 and block 1672 to display a prompt to theoperator to check the magnetometer cable attachments. The program thenreturns as represented at line 1674 to line 1662.

Where the query posed at block 1664 is responded to in the affirmative,then as represented at line 1676 and block 1678, green LED 212′″ atconsole 112″. is illuminated and the program continues as represented atline 1680 and block 1682. At this juncture in the procedure, theoperator will be positioning the magnetometer probe 1124′″ as close aspractical to the implant (s) in order to obtain a maximum magnetometersignal channel differentiation.

The ACF heating assembly actuation next is addressed as represented atline 1684 and block 1686 providing for turning off the electromagnet1544 by actuating the stop button switch 1550 on console 112′″.

The ACF heating assembly actuation next is addressed as represented atline 1688 and block 1690 providing that the ACF heating assembly 94′″ isturned on and, as represented at line 1692 and block 1694 a query isposed as to whether the ACF heating unit is enabled both by thedevelopment of a requisite voltage level, V_(RF) as being greater thanor equal to three volts and the presence of the earlier-describedmagnetometer signal V_(c) as being greater than or equal to three volts.If those ANDed conditions are not met, then as represented at line 1696and block 1698 an error visual cue is provided at display 204′″indicating that the control leads 102′″ are not properly connected tothe control console 112′″. The program then continues as represented atline 1700 and block 1702 to display a prompt advising the operator toturn off the ACF heating unit and check the cable attachment 102′″extending to the console 112′″. The program then reverts to line 1688 asrepresented at line 1704.

Where the query posed at block.1694 results in an affirmativedetermination, then as represented at line 1706 and block 1708, greenLED 211′″ is illuminated and the program continues as represented atline 1710. Line 1710 extends to the query posed at block 1712determining whether the duration for therapy and maximum time allottedfor reading setpoint temperature T_(SP) have been set to correct andintended intervals. These intervals are set by the operator employingthe up/down switches 190′″ and election switch 191′″ in conjunction withdisplay 192′″ on console 112′″. Where the therapy duration is incorrect,then as represented at line 1714 and block 1716 appropriate adjustmentof the control switches 190′″ and 191′″ is made and the program revertsto line 1710 as represented at line 1718.

Where the query posed at block 1712 is responded to in the affirmative,then as represented at line 1720 and block 1722 a determination is madeas to whether the therapy time elapsed indicates zero minutes. Thisreadout is provided at console 112′″ at display 222′″. In the event thatthis display does not register zero minutes, then as represented at line1724 and block 1726, reset button switch 224′″ is actuated and theprogram continues as represented at lines 1728 and 1720. With thetherapy time remaining set at zero, the procedure continues asrepresented at line 1730 and block 1732. Block 1732 reflects theactivity of controller 240′″ (FIG. 54A, 54B) in carrying out adetermination that the conditions established by the illumination ofLEDs 1554, 211′″ and 212′″ at console 112′″ have been satisfied and thesystem now is ready to commence a thermotherapy mode. In the event theready check fails, then as represented at line 1734 and block 1736 anerror cue is published at display 204′″ and, as represented at line 1738and node A the program reverts to line 1628. In the latter regard, nodeA and line 1738 reappear adjacent line 1628.

In the event the query posed at block 1732 results in an affirmativedetermination, then as represented at line 1740 and block 1742thermotherapy, which generally will comprise hyperthermia therapy,commences with the operator actuation of the start therapy button switch220′″ at console 112′″. With this actuation, electromagnet 1544automatically is restarted, ACF heater unit 96′″ and the magnetometer1122′″ are activated. Such actuation of the switch 220′″, will, asrepresented at line 1744 and block 1746 provide for the illumination ofgreen LED 213′″ indicating that therapy is in progress. The procedurethen continues as represented at line 1748 to the query at block 1750determining whether or not the stop therapy button switch 226′″ atconsole 112′″ has been actuated. In the event such actuation hasoccurred, then as represented at line 1751 and block 1752 the AC fieldheating power assembly is turned off; electromagnet 1544 is stopped;green LED 213′″ is turned off and red LED 228″. is illuminated as avisual cue that the therapy has been stopped. The procedure thencontinues as represented at line 1753 and block 1754 at which juncturethe operator determines whether or not therapy is to be resumed. In theevent that it is to be so resumed, then as represented at line 1755 andblock 1756, in order to resume the therapy mode for the duration of theunlapsed therapy, the start therapy switch 220′″ is actuated at controlconsole 112″ which, in turn, causes the turning off of red LED 228′″.The start therapy switch actuation automatically activates the ACFheating assembly 94″. as well as the automatic restarting of theelectromagnet 1544. The program then continues as represented at line1757 which extends to line 1744.

Where the query posed at block 1758 results in a determination thattherapy is not to be resumed, then as represented at line 1758 and node1759 the therapy is ended.

Returning to block 1750, where a determination has been made that thestop therapy switch 226″. has not been actuated, then as represented atline 1760 and block 1761, a query is made as to whether the targetsetpoint temperature T_(SP) has been reached. This target temperaturehas been discussed in conjunction with dashed line 142 in connectionwith FIG. 7. Refer additionally to the ranges provided in conjunctionwith T_(heater) set forth in Table 1. When the target or setpointtemperature has been reached, then as represented at line 1762 and block1764 a determination is made as to whether the maximum time allotted toreach the setpoint temperature T_(SP) has elapsed before that setpointtemperature has been reached. In the event that is not the situation,then as represented at line 1766 and block 1768, the program starts orcommences continuation of therapy duration. In this regard, inasmuch astarget temperature has been reached, if this is the first time it hasbeen reached, then the system starts such therapy duration. However, ifthe setpoint temperature had been earlier reached, then the therapyduration continues for its originally allotted interval. The programthen continues as represented at lines 1770 and block 1772. Block 1772provides for the illumination of green LED 215′″ serving as anindication that target temperature has been reached. The program thencontinues as represented at line 1774 and block 1778 wherein a query isposed determining whether or not the therapy time elapsed has reachedthe selected therapy duration valuation. In the event that it has not,then as represented at line 1780 and block 1782 the time elapsed display222′″ is updated as represented at line 1784 and node B, the programreverts to line 1748. In the latter regard, it may be noted that node Band line 1784 appear in adjacency with line 1748.

Where the query posed at block 1778 results in an affirmativedetermination, then the program continues as represented at line 1786and block 1804. Returning to block 1764, in the event that the maximumtime allocated for reaching target temperature T_(SP), has elapsedbefore the setpoint temperature has been reached, then an errorcondition obtains and is represented at line 1788 and block 1790 anerror is displayed at display 204′″ and the program continues asrepresented at lines 1792 and 1786 to block 1804. Block 1804 providesfor the deactivation of the active components of the system. In thisregard, the ACF heating power system is turned off; electromagnet 1544is turned off; magnetometer 1122′″ is turned off; therapy completedgreen LED 214′″ is illuminated; and green LED 213′″ representing therapyin progress is de-energized. The program then continues as representedat line 1806 and block 1808 wherein pertinent data for the procedureparameters is recorded. It may be recalled that this data can bedisplayed at display 204′″ by the actuation of button switch 206′″. Theprocedure then continues as illustrated at line 1810 extending to node1812 representing a therapy ended stage. TABLE 1 Para- PreferredPreferred meter Description Minimum Maximum Minimum Maximum Units D₁diameter of sensor  0.01 (0.25) 0.50 (12.7) 0.02 0.20 inch (cylindershaped) (0.51 mm) (5.1 mm) (mm) D₂ diameter of sensor  0.01 (0.25) 0.50(12.7) 0.02 0.20 inch (cylinder shaped) (0.51 mm) (5.1 mm) (mm)ΔT_(heate)

heater temperature range 0.1 20 0.1 3 degree around setpoint C.ΔT_(senso)

sensor temperature range 0.1 10 0.1 3 degree around setpoint C. δT₁tissue temperature range 0.1 8 0.1 3 degree around setpoint C. δT_(stent) temperature range of stent 0.1 5 0.1 3 degree around setpointC. δ t₁ heater turn on period 0.01 30 0.05 5 seconds δ t₂ heater turnoff period 0.005 5 0.02 1 seconds (magnetometer sampling period) f₁Frequency range 10K 10 M Hertz H₁ semicylindrical diameter of 0.005(0.13) 0.25 (6.4)  0.010 (0.25) 0.10 (2.5) inch height of sensor (mm) H₂semicylindrical diameter of 0.005 (0.13) 0.25 (6.4)  0.010 (0.25) 0.10(2.5) inch height of heater (mm) L₁ length of Implantable 0.05 (1.3) 4.0 (102) 0.10 (2.5)  2.0 (51) inch heater/sensor (mm) L₂ length ofImplantable 0.05 (1.3)  4.0 (102) 0.10 (2.5)  2.0 (51) inchheater/sensor (mm) L₃ length of Implantable 0.05 (1.3)  4.0 (102) 0.10(2.5)  2.0 (51) inch heater/sensor (mm) L₄ length of stent sensor 0.06(1.5) 1.5 (38)   0.1 (2.5)    1 (25.4) inch (mm) L₅ length of stent 0.12(3)    3 (76)  0.2 (5.1)  2 (51) inch (mm) L₆ length of stent sensor0.03 (.78) 0.75 (19)   0.05 (1.3)   05 (12.7) inch segment (mm)P_(stent) Instantaneous heating 0.05 20 0.1 10 calories/ power generatedwithin second stent P_(heater) Instantaneous heating 0.05 20 0.1 10calories/ power generated within second heater P_(tissue) Instantaneousheating 0.2 100 0.4 25 calories/ power generated within second tissue t₁thickness of heater  0.001 (0.025) 0.20 (5.1)   0.003 (0.075) 0.10 (2.5)inch (mm) t₂ thickness of biocompatible  0.0001 (0.0025) 0.05 (1.3)  0.001 (0.025)  0.03 (0.76) inch coating (mm) t₃ thickness of thermally 0.001 (0.025) 0.20 (5.1)  0.005 (0.13) 0.10 (2.5) inch activatable drugrelease (mm) compound t₄ thickness of end cap  0.001 (0.025) 0.20 (5.1)  0.003 (0.075) 0.10 (2.5) inch (mm) t₅ thickness (diameter) of  0.01(0.25) 0.50 (12.7)  0.03 (0.75) 0.20 (5.1) inch stent sensor (mm) t₆thickness of stent sensor  0.0001 (0.0025) 0.05 (1.3)   0.001 (0.025) 0.03 (0.76) inch support band (mm) t₇ thickness of adhesive  0.0001(0.0025) 0.03 (0.75)  0.001 (0.025) 0.015 (0.38) inch layer (mm) t₈thickness of thermally  0.001 (0.025) 0.20 (5.0)  0.005 (0.13) 0.10(2.5) inch activatable drug release (mm) compound T_(heater) nominalhyperthermia 39 70 40 48 degree therapy temperature for C. heaterT_(stent) nominal hyperthermia 39 70 43 47 degree therapy temperaturefor C. stent T_(ID) target tissue implant 40 45 degree temperature rangefor C. infectious disease T_(BONE) target tissue implant 39 41 degreetemperature range for C. boney tissue repair T_(DRS) nominal releaseagent 39 85 41 50 degree temperature C. TR₁ thermal resistance 5 degreebetween heater and C./ sensor watt TR₂ thickness of thermally 0.5 degreeactivatable drug release C./ compound watt TR₃ thermal resistance 5degree between stent and sensor C./ watt TR₄ preferred thermal 0.5degree resistance between stent C./ and sensor watt W₁ width of heatersegment 0.005 (0.13) 0.25 (6.3)  0.010 (0.25) 0.10 (2.5) inch (mm) W₂distance between heater 0.005 (0.13) 0.25 (6.3)  0.010 (0.25) 0.10 (2.5)inch segments (mm) W₃ exposed length of sensor 0.05 (1.3)  4.0 (102)0.10 (2.5)  2.0 (51) inch (mm) W₄ exposed length of sensor 0.05 (1.3) 4.0 (102) 0.10 (2.5)  2.0 (51) inch (mm) W₅ width of heater coupling 0.02 (0.51)  0.5 (12.7) 0.04 (1)    0.2 (5.1) inch (mm) W₆ width (ordiameter) of  0.01 (0.25) 0.50 (12.7)  0.03 (0.75) 0.20 (5.1) inch stentsensor (mm) W₇ gap between stent sensor 0.005 (0.13) 0.1 (2.5)  0.01(0.25) 0.05 (1.3) inch segments (mm)

As is apparent, the sensor and/or sensor/heater component combination ofthe invention as combined with a magnetometer based temperatureevaluation approach provides the highly desirable, untethered, in vivothermal treatment of tissue. Such tissue may include bone matter, i.e.,boney tissue. In this regard, the sensors may be attached to a bonerepair implant or support component such as a rod, plate or screwallowing such an implant then to be raised to a controlled and slightlyelevated temperature, for example, in a range of from about 39° C. toabout 41° C. The heating can be accomplished by already existingapproaches, such as by microwave radiation, or ultrasound. Such mild buttargeted and accurately controlled temperature elevations serve toaccelerate the rate of bone growth and/or fusion necessary to ultimatebone repair. The untethered nature of the sensors as discussed above,permits an essentially non-invasive repetition of these therapies.

In another embodiment of the invention, a sensor/heater componentcombination, allows controlled heating of the region directlysurrounding a boney injury, wound or tumor site. In this regard, thesensor/heater component combination may be attached to a bone repairimplant or support component or a number of sensor/heater componentcombinations could be placed adjacent to the area to be treated. Thesensor/heater component combination allows an implant or the tissueadjacent to sensor/heater component to be heated, raised to a controlledand slightly elevated temperature, with the absolute temperature rangedepending on a number factors, including but not limited to, the initialbody temperature, the duration of heating used, and the stage of healingof the boney tissue, and such additional factors as discussed previouslyherein.

Implantation of sensors and/or sensor/heater component combinationminimizes the potential for infection present with tethered bonestimulation implants, which are susceptible to infection at the site ofthe tether. Nor does the tissue immediately adjacent to an injured boneneed be exposed by invasive surgery. The minimally invasive implantationof the sensor/heater component allows the sensor/heater componentcombination to remain in place for an extended treatment period. Thesensor/heater component combination can be placed such that the targettissue is directly heated. Additional advantages of the sensor/heatercomponent combination, whether used alone, or in conjunction with otherheating mechanisms is the ability to readily determine the temperatureof the target boney tissue, which cannot be easily done with existinguntethered bone growth stimulators. Due to cytotoxic effects if thetissue is overheated, which could damage boney tissue, the ability tomonitor the temperature of the target tissue allows therapy thatmaximizes the therapeutic benefit by maintaining the target tissue inthe chosen therapy temperature range.

Hyperthermia can be used as a means for inducing immunity or fortreating diseases caused by infectious agents. Particularly for chronicinfections that are recalcitrant to treatment with drugs or otherexisting therapies, an infected individual's immune system could beactivated by using hyperthermia to induce infected cells to presentimmunogenic peptides. In this regard, the sensor/heater component of thepresent invention could be implanted in tissue that harbors thepathogen. Heating of the tissue sufficient to induce heat shock, aspreviously described, would cause infected cells to present immunogenicpeptides derived from the infectious agent, thus activating the immunesystem. Those tissues or organs with relatively high numbers of infectedcells would be preferred targets for the hyperthermia. Examples oftargets include, but are not limited to, the liver or spleen forMycobacterium tuberculosis infections; lymph nodes for HumanImmunodeficiency Virus infections; the liver for Plasmodium or hepatitisvirus infections.

The present invention is superior to currently available methods forinducing immunity to infectious agents using HSPs because it offers moreprecise temperature control of the heat shock than whole organismhyperthermia; focuses the induction of the immune system on a subset ofthe peptides presented by whole organism hyperthermia; induces an immuneresponse against the actual infectious agent present in the organism,rather than against a non-specific agent that exogenous purifiedvaccines would produce; and can be used to treat acute infection forwhich no effective therapy is available.

Since certain changes may be made in the above-described apparatus,method and system without departing from the scope of the inventionherein involved, it is intended that all matter contained in thedescription thereof or shown in the accompanying drawings shall beinterpreted as illustrative and not in a limiting sense.

1-28. (canceled) 29-45. (canceled)
 46. Stent apparatus for positioningwithin the body of a patient, comprising: a metal stent structure havinga contact surface configured for abutting engagement with tissue of saidpatient and formed of material responsive to an alternating field basedenergy applied externally of said body to elevate in temperature; and anuntethered sensor with a soft ferrite component assembly formulated withoxides of Fe, Mn and Zn to exhibit a Curie point temperature at ahyperthermia based level.
 47. The stent apparatus of claim 46 in which:said ferrite component is fixed to said stent structure contact surface.48. The stent apparatus of claim 46 further comprising a flexiblesecurement band agalvanic with respect to said metal stent structure andtensionally surmounting said metal stent structure and said ferritecomponent assembly.
 49. The stent apparatus of claim 46 in which saidferrite component assembly is coated with a biocompatible electricallyinsulative conformal layer.
 50. The stent apparatus of claim 46 inwhich: said stent structure is generally cylindrically shaped; and saidferrite component assembly comprises a first discrete ferrite componentfixed to said contact surface, and a second ferrite component fixed tosaid contact surface at a location generally diametrically opposite fromthe location of said first ferrite component.
 51. The stent apparatus ofclaim 46 further comprising a thermally activatable release agentcoating extending over said metal stent structure, effective to limitrestenosis when said stent structure is elevated in temperature.
 52. Thestent apparatus of claim 46 in which: said ferrite component assemblycomprises a soft ferrite containing about 49 wt % iron, about 15 wt%zinc, about 9 wt % manganese and about 27 wt % oxygen, said Curie pointtemperature being about 44.5° C.
 53. The stent apparatus of claim 46 inwhich: said ferrite component assembly comprises a soft ferriteformulated with about 49 wt % iron, about 15 wt % zinc, about 9 wt %manganese and about 27 wt % oxygen and exhibits a Curie pointtemperature of about 44.5° C. 54-65. (canceled)